Derrick Gingery

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Family Practice News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Family Practice News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Family Practice News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Clinical Psychiatry News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Clinical Psychiatry News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Clinical Psychiatry News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration advisory committee members have recommended lamotrigine extended-release tablets as a monotherapy for partial seizures, relying on the knowledge that the immediate-release version of the drug works for the indication.

The Peripheral and Central Nervous System Drugs Advisory Committee found that substantial evidence had been submitted to support the recommendation, but not because of the novel clinical trial design GlaxoSmithKline (GSK) utilized for the supplemental indication. It was the fact that the immediate-release (IR) version of the same drug already had been approved for monotherapy that swayed a majority of the committee during its March 10 session.

The committee voted 10 to 2 in favor of the evidence of effectiveness for Lamictal XR (extended release). There was one abstention and one member absent for the vote. All the committee members who voted in favor said knowing the immediate-release version was effective affected their decision.

Acting Committee Chairman Dr. Britt Anderson, an assistant professor in the psychology department at the University of Waterloo, Ontario, said knowing about the immediate-release version was a factor, but not critical to his "yes" vote.

Dr. Phillip Pearl, division chief of general child neurology at Children’s National Medical Center, Washington, D.C., said after the vote that "the [immediate release] made my decision feel rational, and I could not come up with a strong-enough feeling to refute that."

The Food and Drug Administration, in a sense, held the same belief about Lamictal XR as did the committee members: In its premeeting briefing documents, Division of Neurology Products Director Dr. Russell Katz said the agency’s prior belief is high that Lamictal XR likely will be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy.

Historical design okay, but data still a problem. Throughout the meeting, committee members struggled to determine the validity of the novel trial design that GSK had utilized in an effort to prove safety and efficacy of the extended-release version as monotherapy.

The study design relied on a historical control, and most of the concerns from the FDA reviewers and committee members focused on the differences between the patient populations of the new study and the control dataset.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European nations, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical control.

Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria, that is, they did not see reduced symptoms on the study drug, than did non-U.S. patients.

Committee members did decide the historical trial design was acceptable, voting 14 to 0 in favor of a positive recommendation.

But when it came time to decide on Lamictal XR’s effectiveness, most committee members could not reach a recommendation based on the evidence that had been submitted. They relied on their clinical experience.

Dr. William Theodore, chief of the clinical epilepsy section at the National Institute of Neurological Disorders and Stroke, said there was an enormous bias among clinicians when voting because they already know the drug works.

"It would be hard to come up with a rational argument to say that ... the controlled release doesn’t work as monotherapy," Dr. Theodore said. "I can’t come up with a reasonable doubt in this context."

The committee strongly reiterated its feelings about the trial’s problems shortly after the vote was taken, when Dr. Norman Hershkowitz, a team leader in the Division of Neurology Products, asked the members whether their thinking would have been different if there were not so many problems with GSK’s clinical trial.

Committee members resoundingly said they would not have had to rely on their prior knowledge of the immediate-release version of the drug. Dr. David Treiman, epilepsy center director at the Barrow Neurological Institute in Phoenix, who voted "no," said he would have changed his vote on the question to "yes."

Neurology division has never accepted a historical control design. GSK submitted its supplemental new drug application (sNDA) for Lamictal XR as a monotherapy treatment for partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties.

The FDA has been considering the historical controls question for several years, and its decision could affect approval of several other drugs in late-stage trials seeking similar monotherapy indications.

Used with permission from "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

Food and Drug Administration reviewers think Lamictal XR may be effective as a monotherapy for partial seizures, but they identified problems with the novel historical control trial design, including issues with U.S. versus ex-U.S. populations, that may have prevented a definitive conclusion.

Members of the Peripheral and Central Nervous System Drugs Advisory Committee seem likely to spend most of their March 10 meeting considering questions about the methodology used in the Lamictal XR (lamotrigine extended-release tablets) trial, before deciding whether it is effective as a monotherapy in patients aged 13 years and older.

GlaxoSmithKline compared its new treatment group with data from control groups in eight monotherapy studies of anticonvulsants previously completed. The historical data and statistical method was outlined in a white paper developed by researchers from the University of Pennsylvania.

A historical control study design has never been accepted by the Division of Neurology Products, even if the goal was to show superiority, because of interpretation difficulties, according to FDA briefing documents.

The FDA is actually fairly confident that Lamictal XR could be an effective monotherapy, in part because it already is approved as an adjunctive therapy and its immediate-release cousin has been shown to be effective as a monotherapy, division director Dr. Russell Katz said in the briefing memo.

The primary difficulty with the design is a "lack of assurance that the patients in the control group and the treated group are ‘identical,’ " Dr. Katz said in the briefing.

Reviewers said in the clinical and statistical review that they were not convinced of the generalizability of the drug’s non-U.S. data to historical U.S. patients. The agency found several issues in which the control population was not comparable to the treatment population, yet reviewers still indicated that, after adjustments, there was evidence of Lamictal XR’s efficacy.

GSK conducted its pivotal LAM30055 study of Lamictal XR in seven countries, including South American and Eastern European states, as well as the United States. The control group contained nearly all U.S. patients, while the treatment group contained about 25% U.S. patients, a group not designed to stand alone in an analysis with the historical controls. Reviewers said it was a problem because a higher percentage of U.S. patients met escape criteria – that is, they did not see reduced symptoms on study drug – than non-U.S. patients.

Reviewers also cited a time difference in comparing the control and treatment groups.

"The span of the pseudoplacebo population ranges from approximately 1992 to 2001," reviewers said in the briefing document. "In the oldest white paper study the pseudoplacebo patients will be almost a generation older than the study population."

Multiple Escapes and Other Study Problems

The control group population also allowed patients to use up to two background antiepileptic drugs, while the treatment group was allowed only one stable background antiepileptic drug. The agency said in its briefing that patients on multiple antiepileptic drugs can be more prone to escape events. Those on one stable monotherapy also have a lower chance of nonresponse to the study drug, the agency said.

Still, after adjusting to look at only those control-group patients on one antiepileptic drug, the agency concluded Lamictal XR was superior.

There also were concerns about underreporting escapes in the trial. After errors were found, GSK retrained study site monitors and other personnel and performed a post-hoc analysis that corrected some of the issues.

Escape events were grouped into four categories covering various incidents of increased or worsening seizures. Reviewers found that the trial had no incidents reported of criterion No. 4, which was clinically significant prolongation of generalized tonic-clonic seizures. They said its absence made comparisons with the control more difficult.

"It was uncertain how to adequately assess the potential bias due to under-reporting criterion No. 4 events," reviewers said in the briefing.

Ethical Issues Will Be Addressed First

GSK submitted its supplemental new drug application for monotherapy treatment of partial seizures in late March 2010. The user fee date was extended from the end of January to April 30 after the FDA requested additional analyses and datasets.

One of the primary reasons for the questions to the advisory committee is the ethical dilemma of using a placebo-controlled monotherapy study in patients with partial seizures. If the committee decides that design is ethical, it will skip the next question asking whether the historical control statistical approach is acceptable. In all, most of the remaining questions, which concern the study methodology, including use of domestic and foreign data, could be rendered moot.

The final question deals with the effectiveness of Lamictal XR as a monotherapy.

The FDA has been considering the historical controls question for several years and its decision could affect several other drugs in late-stage trials seeking similar monotherapy indications.

Elsevier Global Medical News and "The Pink Sheet" are published by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval.

"The Pink Sheet" and this news organization are both owned by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval. ☐

"The Pink Sheet" and this publication are both published by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval. ☐

"The Pink Sheet" and this publication are both published by Elsevier.

SILVER SPRING, MD. – The Food and Drug Administration appeared to be searching for a way to limit the clinical trial requirements for generic biologic therapies – or biosimilars – during a 2-day public hearing on implementing an approval pathway for the products.

In preparing for the hearing, the FDA hinted it might be willing to consider the possibility that a biosimilar application might not require any clinical trials.

Many presenters, including several manufacturers of approved biologic therapies, insisted that biosimilarity could not be established definitively without a clinical trial because analytical methods are not yet sophisticated enough. Others, including some generic pharmaceutical manufacturers, argued the agency should use discretion in deciding whether trials would be necessary.

FDA officials tried to carve out a middle ground between the two camps. Dr. Steven Kozlowski, director of the Office of Biotechnology Products within the agency’s Center for Drug Evaluation and Research (CDER), and Dr. John Jenkins, director of the CDER Office of New Drugs, appeared through their questioning to indicate a strict and extensive clinical data requirement might not get many biosimilars to the market, but an overly lax standard might not uncover some safety concerns before marketing begins.

Bruce Babbitt, Ph.D., principal consultant at Parexel Consulting, said FDA’s questions and statements during the hearing seemed to indicate the agency would be willing to be flexible with requiring trials, unlike in Europe, where trials are required for all applications.

"FDA might be open to establishing comparability using [pharmacokinetic/pharmacodynamic] studies in humans head to head with a reference [product]," he said.

Dr. Babbitt argued during his formal presentation the "totality of the data" of biologic products already establishes a base for proving biosimilarity and should not be ignored.

"We consider it important to balance the value and relevance of these data against the need for clinical safety and efficacy data particularly where minor or modest differences between the biosimilar and reference products are unlikely to translate into any meaningful differences in the clinic," Dr. Babbitt said in written testimony.

Dr. Kozlowski asked if there is a way to use the totality of the data in determining what studies would be required.

"Is there a way of incorporating that totality of the data or prior knowledge to think about what the impact on clinical studies are because usually the impact is some big-step function?" he asked Dr. Babbitt.

The totality of data helps either streamline or expand the data sponsors needed for their application, Dr. Babbitt said.

Dr. Jenkins also pointed out suggestions from innovator companies that could be excessive and likely not allow for many biosimilar approvals.

"For your clinical head-to-head trials you wanted a demonstration of equivalence, and you wanted a small confidence interval, you recommend equivalence for safety and efficacy and the surrogate endpoints are not acceptable unless they’ve been clinically validated," Dr. Jenkins said to Dr. Michael Wenger, global clinical lead at Roche. "Is that really an achievable standard ... or is that essentially closing the door for a biosimilar?"

Dr. Wenger argued the drugs should be assessed on a case-by-case basis.

The issue of extrapolation – allowing a biosimilar to be used in all the indications of its reference product after being thoroughly studied in only one – generated concerns about the extent of the clinical data needed. The clinical trial program for a biosimilar would be extremely large if a sponsor was required to produce data showing similarity for each indication it wanted in an application.

Dr. Kozlowski questioned whether it was possible to extrapolate some indications using data for others.

"Say you had the two most different indications in a product that had five indications and you explore those two. Do you believe you could extrapolate the other three?" he asked.

The idea would depend on the clinical benefit achieved by the innovator drug, according to Dr. Wenger. If it was a benefit that could be achieved easily, it may be possible, he said, adding that a more complicated benefit, like overall survival in oncology, would require more work.

Dr. Kozlowski asked Vijay Tammara, Ph.D., vice president of regulatory affairs at Nuron Biotech Inc., whether requiring pharmacokinetic and pharmacodynamic studies could be sufficient premarket, saving immunogenicity testing for the postmarketing studies.

That concept came up again later, during questioning of Sara Radcliffe, executive vice president of health for the Biotechnology Industry Organization (BIO) when Dr. Kozlowski asked whether it would be useful to use pre-marketing data to establish biosimilarity and postmarketing data to test interchangeability.

Ms. Radcliffe said that idea could be possible if an interchangeability determination was not possible before marketing.

Despite the discussion that appeared to indicate a potential for flexibility at FDA, panel members did not give a definitive answer about which way they were leaning.

Dr, Kozlowski’s questions sometimes presented the case for stronger clinical trial requirements. Rasmus Rojkjaer testified on behalf of the Generic Pharmaceutical Association that data from non-U.S. referenced products should be allowed for applications to the FDA and trials should not be more extensive than those required for an innovator product.

Dr. Kozlowski said there had been cases in Europe where clinical trials were shown to be important because they uncovered information that changed the product’s development. He asked about Mr. Rojkjaer’s view of the idea.

Mr. Rojkjaer reiterated that biosimilar applications should not have over-arching rules governing their reviews.

"I think clinical trials has its role to play, but forcing the industry to fit into a one-[size]-fits-all kind of approach I think would seriously keep the development of these biogeneric compounds back," he said.

When Dr. James Roach, chief medical officer of Momenta Pharmaceuticals Inc., argued the trials should be positioned as supportive to existing data, Dr. Jenkins said the agency still has to decide how it will ensure biosimilars are actually similar enough to the reference product.

"We heard a lot of comments yesterday from patient groups and prescribers that they wanted to be very certain that the biosimilar would be highly similar to the clinical effect of the branded product," Dr. Jenkins said. "How do you reconcile those two viewpoints as far as where we should set the bar on determining the role of the clinical trials in establishing that there’s no clinically meaningful difference as the statute requires between the biosimilar and the reference product?"

Dr. Roach said he thought it was possible to provide a limited clinical data set in addition to the existing data package to gain a product approval. ☐

"The Pink Sheet" and this publication are both published by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, 'You know what? We really do have market failure, we need government intervention in a meaningful way,'” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. “But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services' Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that authority in the development of the H5N1 and H1N1 influenza vaccines, and certainly could try it again.

“The Pink Sheet” and Family Practice News are both owned by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, 'You know what? We really do have market failure, we need government intervention in a meaningful way,'” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. “But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services' Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that authority in the development of the H5N1 and H1N1 influenza vaccines, and certainly could try it again.

“The Pink Sheet” and Family Practice News are both owned by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA). The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, 'You know what? We really do have market failure, we need government intervention in a meaningful way,'” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. “But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services' Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that authority in the development of the H5N1 and H1N1 influenza vaccines, and certainly could try it again.

“The Pink Sheet” and Family Practice News are both owned by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee on June 9.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus. The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, ‘You know what? We really do have market failure, we need government intervention in a meaningful way,’ ” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. "But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that the authority in the development of the H5N1 and H1N1 influenza vaccines and certainly could try it again.

“I have worked in public-private partnerships where we have gotten companies together to advance general societal goals and they’ve had to be extremely lawyer-intensive on the antitrust issue,” Dr. Woodcock said. “So there’s no doubt I think it’s a barrier to working together to advance broader goals.”

“The Pink Sheet” and Elsevier Global Medical News are both owned by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee on June 9.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus. The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, ‘You know what? We really do have market failure, we need government intervention in a meaningful way,’ ” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. "But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that the authority in the development of the H5N1 and H1N1 influenza vaccines and certainly could try it again.

“I have worked in public-private partnerships where we have gotten companies together to advance general societal goals and they’ve had to be extremely lawyer-intensive on the antitrust issue,” Dr. Woodcock said. “So there’s no doubt I think it’s a barrier to working together to advance broader goals.”

“The Pink Sheet” and Elsevier Global Medical News are both owned by Elsevier.

WASHINGTON — Government incentives probably will be necessary to rejuvenate the drug development pipeline for antibiotics, Dr. Janet Woodcock, chief medical officer of the Food and Drug Administration, testified before a congressional committee on June 9.

The number of investigational new drug applications for antibiotics has declined since 1987 but has started to increase again over the last 3 years, Dr. Woodcock told the House Energy and Commerce Committee, Subcommittee on Health. But as more bacteria develop resistance to antibiotics, more and new therapies are necessary, she added.

Drug-resistant infections cost $35 billion a year in the United States, yet many companies do not find antibiotics a financially viable product since they involve a limited course of treatment and have generic competition, among other factors.

There also is confusion among the scientific pathway for approval. Dr. Woodcock said that new guidance documents on clinical trial designs are in the works but acknowledged that they may not be enough to push the industry to increase drug development.

“It will likely also take the development of incentives in order to stimulate the development of new antibacterial drugs so that we have new therapeutic options” to treat current and future resistant pathogens, Dr. Woodcock said in written testimony.

Recognizing that government intervention is necessary to help solve the problem is a giant step forward, said Dr. Barry Eisenstein, senior vice president of scientific affairs at Cubist Pharmaceuticals, who also testified at the hearing.

Cubist currently markets daptomycin (Cubicin) for the treatment of skin and skin structure infections caused by certain susceptible strains of Gram-positive microorganisms, including methicillin-resistant Staphylococcus aureus. The company currently has three antibiotic drugs in development, he said.

“To me, this is almost a breakthrough to see a branch of government actually saying, ‘You know what? We really do have market failure, we need government intervention in a meaningful way,’ ” Dr. Eisenstein said in an interview.

In his testimony, Dr. Eisenstein supported policies for antibiotics modeled on the programs that have sparked development of drugs for rare diseases and expanded the knowledge about pediatric uses.

“New incentives must be designed so that they encourage investment in activities across the research spectrum, from basic research to clinical trials, and target as broad a range of scientists, entrepreneurs, large and small companies, and life science investors as possible,” Dr. Eisenstein said in written testimony.

Dr. Woodcock warned that incentives still have to be considered in the context of restrictions that may be required once the drugs are on the market because the ultimate goal is limiting antibiotic use.

“If we contemplated a pipeline that would end up [where] antimicrobials would only be used in niche situations, where they were really needed, that would be even a further disincentive,” she said. "But you have to think about that as a goal to preserve the effect of that for a long time.”

Robin Robinson, Ph.D., director of the Department of Health and Human Services’ Biomedical Advanced Research and Development Authority, said that industry has indicated in the past that liability protections would be very helpful and important in moving drugs along the pipeline.

Dr. Robinson and Dr. Woodcock also said that easing antitrust laws in certain cases to encourage companies to work together was worth exploring. Dr. Robinson noted that BARDA used that the authority in the development of the H5N1 and H1N1 influenza vaccines and certainly could try it again.

“I have worked in public-private partnerships where we have gotten companies together to advance general societal goals and they’ve had to be extremely lawyer-intensive on the antitrust issue,” Dr. Woodcock said. “So there’s no doubt I think it’s a barrier to working together to advance broader goals.”

“The Pink Sheet” and Elsevier Global Medical News are both owned by Elsevier.