FDA panel supports easing rosiglitazone restrictions

SILVER SPRING, MD. – Reassured by the results of a reanalysis of data from a cardiovascular safety trial of rosiglitazone, the majority of a Food and Drug Administration advisory panel recommended either loosening or lifting the restrictions placed on prescribing of the type 2 diabetes drug in 2010.

At a June 6 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, 13 panel members voted to modify the Risk Evaluation and Mitigation Strategy (REMS) required for the drug and seven recommended that it be removed altogether. Of the remaining six panelists, five recommended that the REMS be continued as it currently exists and one panelist, the consumer representative, voted to withdraw the drug from the market.

The FDA convened the 2-day meeting to review the results of the readjudication of data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial, conducted by the Duke Clinical Research Institute (DCRI), Durham, N.C., which was commissioned to do the reanalysis by rosiglitazone manufacturer GlaxoSmithKline, which was directed to do so by the FDA.* The DCRI reanalysis found no significant differences in the composite of CV death, MI, or stroke; numerically fewer CV deaths and numerically fewer strokes in the rosiglitazone arm; and a lower risk of all cause death. There were more MIs in the rosiglitazone arm, but the difference was not significant.

On the basis of those results, the panel did not conclude that the data showed there was no increased cardiovascular risk, but generally felt reassured by the results. One of the cardiologists on the panel, Dr. Marvin Konstam, professor of medicine, Tufts University, Boston, said that the readjudicated results of RECORD "do not remove my concern about the cardiovascular safety of rosiglitazone, but in my mind, they move the needle in a direction that seems to me is appropriate to shift the burden of decision making for prescribing this drug to physicians in terms of interpreting the entirety of the data."Dr. Konstam voted for modification of the REMS.

"I still think there’s unresolved concern about an adverse cardiovascular effect or effects, but I don’t wish to deprive qualified patients rosiglitazone as an option, even in this context," said Dr. Robert Smith, an endocrinologist who is professor of medicine at Brown University, Providence, R.I.., who voted that the REMS should stay in place.*

Endocrinologist Dr. Ellen Seely, professor of medicine at Harvard Medical School, Boston, was among those voting to remove the REMS. Although she was not convinced that there was no such risk associated with rosiglitazone, "I don’t think we have data to support there is a cardiovascular risk," she said. There is a great need for drugs that type 2 diabetes that do not cause hypoglycemia, and it is helpful to have options for those patients who have exhausted most treatment options, who may not want to take pioglitazone because of the association with bladder cancer, or who are resistant to taking insulin, she added.

Under the REMS, which was fully implemented in May 2011, prescribers of rosiglitazone must be certified, and the drug can only be dispensed from one of four speciality mail-order pharmacies to patients with documentation to prove that the prescriber has discussed with them the potential increased risk of MI associated with the drug – and that they are either already taking rosiglitazone, or are unable to achieve glycemic control on other medications, and "in consultation with their health care provider, have decided not to take pioglitazone for medical reasons."

The FDA announced the REMS would be required in September 2010, several months after the same advisory panels met to discuss data from meta-analyses and other studies evaluating the CV safety of rosiglitazone, and the majority recommended restrictions on prescribing and a significant proportion recommending that it be taken off the market. The FDA also requested that GSK commission an independent blinded readjudication of RECORD, an open-label CV safety trial conducted outside of the United States, to address concerns of the panelists at the July 2010 meeting about the integrity and reliability of the data because of missing data and other issues.

The panel was satisfied with the results and largely agreed that these concerns were allayed and that the RECORD results could be considered along with the other studies that provided safety data on rosiglitazone, although none were ideal.

One of the panelists who voted to keep the REMS as it exists, Dr. Maria Suarez-Almazor of University of Texas MD Anderson Cancer Center, Houston, said she voted for no change because "there were consistent signals for MI in the observational data and also in the RECORD trial," and although they were not statistically significant, she did not see a clear benefit of using this drug over pioglitazone, other than the bladder cancer issue.

In 2011, 59% of all available rosiglitazone products, including combination products that contain the drug, were in retail pharmacies, and 34% were available through mail-order pharmacies. In 2012, 97% were in mail-order pharmacies and less than 0.1% were in retail pharmacies, according to the FDA. Between July 2007 and July 2010, 1.6 million patients received prescriptions for rosiglitazone, dropping to about 4,600 patients in 2012. Based on national prescription data, between May 2011 and December 2012, after the REMS was put in place, rosiglitazone was most commonly prescribed by physicians in family or general practice (about 52% of prescribers) and internists (about 32%), followed by endocrinologists (almost 4%), according to the FDA. These proportions are similar to the period from 2007, up until the REMS.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

In a statement released by GSK shortly after the panel meeting ended, Dr. James Shannon, GSK’s chief medical officer, said that the company "will continue to work with the FDA as it considers the recommendation of the committee." Rosiglitazone was approved by the FDA in 1999. Earlier, on the first day of the meeting, GSK indicated that it had no plans to market rosiglitazone or any products containing it.

[email protected]

Correction, 06/07/2013: An earlier version of this story misstated the organization that commissioned the reanalysis of the data.

Correction, 06/12/2013: An earlier version of Dr. Nissen's video interview incorrectly stated that the rest of the world had banned rosiglitazone. The drug remains available in some countries, in addition to the United States.

Correction, 06/12/2013: An earlier version of this story misstated Dr. Smith's vote.

SILVER SPRING, MD. – Reassured by the results of a reanalysis of data from a cardiovascular safety trial of rosiglitazone, the majority of a Food and Drug Administration advisory panel recommended either loosening or lifting the restrictions placed on prescribing of the type 2 diabetes drug in 2010.

At a June 6 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, 13 panel members voted to modify the Risk Evaluation and Mitigation Strategy (REMS) required for the drug and seven recommended that it be removed altogether. Of the remaining six panelists, five recommended that the REMS be continued as it currently exists and one panelist, the consumer representative, voted to withdraw the drug from the market.

The FDA convened the 2-day meeting to review the results of the readjudication of data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial, conducted by the Duke Clinical Research Institute (DCRI), Durham, N.C., which was commissioned to do the reanalysis by rosiglitazone manufacturer GlaxoSmithKline, which was directed to do so by the FDA.* The DCRI reanalysis found no significant differences in the composite of CV death, MI, or stroke; numerically fewer CV deaths and numerically fewer strokes in the rosiglitazone arm; and a lower risk of all cause death. There were more MIs in the rosiglitazone arm, but the difference was not significant.

On the basis of those results, the panel did not conclude that the data showed there was no increased cardiovascular risk, but generally felt reassured by the results. One of the cardiologists on the panel, Dr. Marvin Konstam, professor of medicine, Tufts University, Boston, said that the readjudicated results of RECORD "do not remove my concern about the cardiovascular safety of rosiglitazone, but in my mind, they move the needle in a direction that seems to me is appropriate to shift the burden of decision making for prescribing this drug to physicians in terms of interpreting the entirety of the data."Dr. Konstam voted for modification of the REMS.

"I still think there’s unresolved concern about an adverse cardiovascular effect or effects, but I don’t wish to deprive qualified patients rosiglitazone as an option, even in this context," said Dr. Robert Smith, an endocrinologist who is professor of medicine at Brown University, Providence, R.I.., who voted that the REMS should stay in place.*

Endocrinologist Dr. Ellen Seely, professor of medicine at Harvard Medical School, Boston, was among those voting to remove the REMS. Although she was not convinced that there was no such risk associated with rosiglitazone, "I don’t think we have data to support there is a cardiovascular risk," she said. There is a great need for drugs that type 2 diabetes that do not cause hypoglycemia, and it is helpful to have options for those patients who have exhausted most treatment options, who may not want to take pioglitazone because of the association with bladder cancer, or who are resistant to taking insulin, she added.

Under the REMS, which was fully implemented in May 2011, prescribers of rosiglitazone must be certified, and the drug can only be dispensed from one of four speciality mail-order pharmacies to patients with documentation to prove that the prescriber has discussed with them the potential increased risk of MI associated with the drug – and that they are either already taking rosiglitazone, or are unable to achieve glycemic control on other medications, and "in consultation with their health care provider, have decided not to take pioglitazone for medical reasons."

The FDA announced the REMS would be required in September 2010, several months after the same advisory panels met to discuss data from meta-analyses and other studies evaluating the CV safety of rosiglitazone, and the majority recommended restrictions on prescribing and a significant proportion recommending that it be taken off the market. The FDA also requested that GSK commission an independent blinded readjudication of RECORD, an open-label CV safety trial conducted outside of the United States, to address concerns of the panelists at the July 2010 meeting about the integrity and reliability of the data because of missing data and other issues.

The panel was satisfied with the results and largely agreed that these concerns were allayed and that the RECORD results could be considered along with the other studies that provided safety data on rosiglitazone, although none were ideal.

One of the panelists who voted to keep the REMS as it exists, Dr. Maria Suarez-Almazor of University of Texas MD Anderson Cancer Center, Houston, said she voted for no change because "there were consistent signals for MI in the observational data and also in the RECORD trial," and although they were not statistically significant, she did not see a clear benefit of using this drug over pioglitazone, other than the bladder cancer issue.

In 2011, 59% of all available rosiglitazone products, including combination products that contain the drug, were in retail pharmacies, and 34% were available through mail-order pharmacies. In 2012, 97% were in mail-order pharmacies and less than 0.1% were in retail pharmacies, according to the FDA. Between July 2007 and July 2010, 1.6 million patients received prescriptions for rosiglitazone, dropping to about 4,600 patients in 2012. Based on national prescription data, between May 2011 and December 2012, after the REMS was put in place, rosiglitazone was most commonly prescribed by physicians in family or general practice (about 52% of prescribers) and internists (about 32%), followed by endocrinologists (almost 4%), according to the FDA. These proportions are similar to the period from 2007, up until the REMS.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

In a statement released by GSK shortly after the panel meeting ended, Dr. James Shannon, GSK’s chief medical officer, said that the company "will continue to work with the FDA as it considers the recommendation of the committee." Rosiglitazone was approved by the FDA in 1999. Earlier, on the first day of the meeting, GSK indicated that it had no plans to market rosiglitazone or any products containing it.

[email protected]

Correction, 06/07/2013: An earlier version of this story misstated the organization that commissioned the reanalysis of the data.

Correction, 06/12/2013: An earlier version of Dr. Nissen's video interview incorrectly stated that the rest of the world had banned rosiglitazone. The drug remains available in some countries, in addition to the United States.

Correction, 06/12/2013: An earlier version of this story misstated Dr. Smith's vote.

SILVER SPRING, MD. – Reassured by the results of a reanalysis of data from a cardiovascular safety trial of rosiglitazone, the majority of a Food and Drug Administration advisory panel recommended either loosening or lifting the restrictions placed on prescribing of the type 2 diabetes drug in 2010.

At a June 6 meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee, 13 panel members voted to modify the Risk Evaluation and Mitigation Strategy (REMS) required for the drug and seven recommended that it be removed altogether. Of the remaining six panelists, five recommended that the REMS be continued as it currently exists and one panelist, the consumer representative, voted to withdraw the drug from the market.

The FDA convened the 2-day meeting to review the results of the readjudication of data from the RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial, conducted by the Duke Clinical Research Institute (DCRI), Durham, N.C., which was commissioned to do the reanalysis by rosiglitazone manufacturer GlaxoSmithKline, which was directed to do so by the FDA.* The DCRI reanalysis found no significant differences in the composite of CV death, MI, or stroke; numerically fewer CV deaths and numerically fewer strokes in the rosiglitazone arm; and a lower risk of all cause death. There were more MIs in the rosiglitazone arm, but the difference was not significant.

On the basis of those results, the panel did not conclude that the data showed there was no increased cardiovascular risk, but generally felt reassured by the results. One of the cardiologists on the panel, Dr. Marvin Konstam, professor of medicine, Tufts University, Boston, said that the readjudicated results of RECORD "do not remove my concern about the cardiovascular safety of rosiglitazone, but in my mind, they move the needle in a direction that seems to me is appropriate to shift the burden of decision making for prescribing this drug to physicians in terms of interpreting the entirety of the data."Dr. Konstam voted for modification of the REMS.

"I still think there’s unresolved concern about an adverse cardiovascular effect or effects, but I don’t wish to deprive qualified patients rosiglitazone as an option, even in this context," said Dr. Robert Smith, an endocrinologist who is professor of medicine at Brown University, Providence, R.I.., who voted that the REMS should stay in place.*

Endocrinologist Dr. Ellen Seely, professor of medicine at Harvard Medical School, Boston, was among those voting to remove the REMS. Although she was not convinced that there was no such risk associated with rosiglitazone, "I don’t think we have data to support there is a cardiovascular risk," she said. There is a great need for drugs that type 2 diabetes that do not cause hypoglycemia, and it is helpful to have options for those patients who have exhausted most treatment options, who may not want to take pioglitazone because of the association with bladder cancer, or who are resistant to taking insulin, she added.

Under the REMS, which was fully implemented in May 2011, prescribers of rosiglitazone must be certified, and the drug can only be dispensed from one of four speciality mail-order pharmacies to patients with documentation to prove that the prescriber has discussed with them the potential increased risk of MI associated with the drug – and that they are either already taking rosiglitazone, or are unable to achieve glycemic control on other medications, and "in consultation with their health care provider, have decided not to take pioglitazone for medical reasons."

The FDA announced the REMS would be required in September 2010, several months after the same advisory panels met to discuss data from meta-analyses and other studies evaluating the CV safety of rosiglitazone, and the majority recommended restrictions on prescribing and a significant proportion recommending that it be taken off the market. The FDA also requested that GSK commission an independent blinded readjudication of RECORD, an open-label CV safety trial conducted outside of the United States, to address concerns of the panelists at the July 2010 meeting about the integrity and reliability of the data because of missing data and other issues.

The panel was satisfied with the results and largely agreed that these concerns were allayed and that the RECORD results could be considered along with the other studies that provided safety data on rosiglitazone, although none were ideal.

One of the panelists who voted to keep the REMS as it exists, Dr. Maria Suarez-Almazor of University of Texas MD Anderson Cancer Center, Houston, said she voted for no change because "there were consistent signals for MI in the observational data and also in the RECORD trial," and although they were not statistically significant, she did not see a clear benefit of using this drug over pioglitazone, other than the bladder cancer issue.

In 2011, 59% of all available rosiglitazone products, including combination products that contain the drug, were in retail pharmacies, and 34% were available through mail-order pharmacies. In 2012, 97% were in mail-order pharmacies and less than 0.1% were in retail pharmacies, according to the FDA. Between July 2007 and July 2010, 1.6 million patients received prescriptions for rosiglitazone, dropping to about 4,600 patients in 2012. Based on national prescription data, between May 2011 and December 2012, after the REMS was put in place, rosiglitazone was most commonly prescribed by physicians in family or general practice (about 52% of prescribers) and internists (about 32%), followed by endocrinologists (almost 4%), according to the FDA. These proportions are similar to the period from 2007, up until the REMS.

The FDA usually follows the recommendations of its advisory panels. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting.

In a statement released by GSK shortly after the panel meeting ended, Dr. James Shannon, GSK’s chief medical officer, said that the company "will continue to work with the FDA as it considers the recommendation of the committee." Rosiglitazone was approved by the FDA in 1999. Earlier, on the first day of the meeting, GSK indicated that it had no plans to market rosiglitazone or any products containing it.

[email protected]

Correction, 06/07/2013: An earlier version of this story misstated the organization that commissioned the reanalysis of the data.

Correction, 06/12/2013: An earlier version of Dr. Nissen's video interview incorrectly stated that the rest of the world had banned rosiglitazone. The drug remains available in some countries, in addition to the United States.

Correction, 06/12/2013: An earlier version of this story misstated Dr. Smith's vote.