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PHILADELPHIA – Several different generic lamotrigine products proved pharmacologically and clinically equivalent to Lamictal, the brand-name, reference form of lamotrigine, in three separate, prospective, randomized trials run by two independent groups. These results that should lay to rest lingering concerns by physicians and patients that generic lamotrigine poses any risk to patients, agreed a panel of experts speaking at a session at the annual meeting of the American Epilepsy Society.
The findings, which confirmed the standards now set by the Food and Drug Administration for deeming generic products equivalent to their reference product, should also reassure physicians and patients more broadly about the reliability of the generic forms of most other antiepileptic drugs as well as generic drugs used for virtually all indications across the range of medical practice, the panelists said.
The results of these three new studies “show that generic drugs have the same quality as the reference-listed drugs in patients with epilepsy,” said Dr. Wenlei Jiang, acting deputy director of the FDA’s Office of Research Standards and Office of Generic Drugs. Dr. Jiang coauthored one of the new studies.
“We were a skeptical group going into our studies,” said Dr. Michael Privitera, coprincipal investigator for the other two new studies. “We were not sure that these drugs [brand-name lamotrigine and various generic products] were really the same. We were shocked at how equivalent they were. It wasn’t that the differences [among their pharmacokinetic profiles] were small; it’s that there was no difference. We could not see any difference,” said Dr. Privitera, professor of neurology and director of the Epilepsy Center at the University of Cincinnati.
“We chose to study lamotrigine because there had been a lot of complaints [about the generic products] and because it is a drug that is very susceptible to drug-drug interactions. There is no reason I can think of why what we found would not extend to all antiepileptic drugs except for phenytoin, which has saturation kinetics and the way the FDA tests drugs in a single-dose study is not appropriate for drugs with saturation kinetics,” Dr. Privitera said in an interview. The implications of the new findings also extend beyond just drugs for epilepsy or other neurologic conditions, he added.
“When you have a very complicated disorder like epilepsy, which has the possibility for drug-drug interactions, and we could show this much quality” in the generic products, it has implications for the entire universe of generic drugs that show equivalence in FDA-mandated testing, Dr. Privitera said.
Randomized trials in epilepsy patients
One of the two studies run by Dr. Privitera and his associates used a single-dose format, and the second used a chronic-dosage format.
The EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy) Single Dose Study enrolled 48 epilepsy patients at any of six U.S. centers. All patients were on an antiepileptic drug other than lamotrigine, and the researchers randomized them to receive single doses of the brand-name reference form of lamotrigine (Lamictal), or either of two generic forms of lamotrigine. Patients received single dosages of each of the three study drugs with a 12-23 day washout period separating each dose (the preferred washout interval was 14 days), with the patients and researchers blinded to which specific product was administered at any time. The researchers selected the two FDA-approved generic products with the most widely divergent profiles based on in vitro dissolution testing and prior pharmacokinetic data supplied to the FDA. Forty-five patients received the scheduled two doses (on two different occasions) of each drug, a total of six test doses administered. The remaining three patients received a single dose of each of the three tested products.
All three products resulted in essentially superimposed concentration-time curves and area under the curve measures with no outliers or serious adverse events seen, Dr. Privitera and his associates reported in a poster presented at the meeting as well as during the session.
The EQUIGEN Chronic Dose Study compared the pharmacokinetic patterns after chronic dosing for 2 weeks with one of the two most disparate lamotrigine generic products. The study enrolled 35 patients with epilepsy at any of six U.S. centers, and 33 patients completed all four treatment periods, which involved a repeated crossover between the two study products. Patients received lamotrigine twice daily and could be on additional antiepileptic drugs or monotherapy; six patients received concomitant enzyme-inducing antiepileptic drugs during the study. The results showed that the area under the curve for both products had 90% confidence intervals of 98%-103%, compared with Lamictal, and they both had a 90% confidence interval for peak plasma concentration of 99%-105%, Dr. Privitera and his associates reported at the session. None of the enrolled patients showed unexpected adverse events, and the two generics produced similar adverse-event profiles.
The third study, BEEP (Bioequivalence in Epilepsy Patients) ran at the University of Maryland, Baltimore, and the results appeared in a journal article published in September (Epilepsia. 2015 Sept;56[9]:1415-24). This study enrolled 34 “generic brittle” epilepsy patients, which meant they had already shown signs of possible sensitivity to switching from Lamictal to generic lamotrigine. The study randomized patients to four consecutive 2-week periods of treatment with either the brand-name or a generic lamotrigine product in a crossover design that was then repeated, and each patient underwent a 12-hour pharmacokinetic analysis after they reached a steady-state drug level with 2 weeks of treatment. The results showed a tight match for both the area under the curve and peak plasma concentration for the generic and brand drugs, said Dr. Tricia Y. Ting, lead investigator for the study and a neurologist and epilepsy specialist at the University of Maryland Medical Center in Baltimore.
“The results could not have been more beautiful. We were quite surprised at how close the generic and brand products were” in their steady-state pharmacokinetic profiles, Dr. Ting said during the session.
The results of the three studies, while reassuring, raise questions as to why some patients nevertheless report problems while taking generic products, noted Dr. Ting. “We need to look outside of bioequivalence, and focus instead on issues such as patient expectations,” she said.
Patient factors
Dr. Joshua J. Gagne, a pharmacoepidemiologist at Brigham and Women’s Hospital in Boston, discussed the role of patient expectations and other patient-specific factors that can affect the safety and efficacy of generic products. He noted that patients can be confused by generic pills that do not have the same size, shape, or color as their brand-name counterparts. “Variations in appearance with generic antiepilepsy drugs is a real problem and may be a barrier to adherence,” he said. In addition, “patients’ out of pocket costs are important drivers of antiepileptic drug adherence,” and may act in favor of generics, he said.
He documented this potential effect in a recent study he published and also summarized while speaking during the session. Dr. Gagne and his associates used a database of more than 19,000 U.S. Medicare patients with epilepsy who began treatment with an antiepileptic drug. The researchers used propensity scoring to match a subset from among the 18,306 patients who started on a generic drug and the 1,454 patients who started on a brand-name drug. In the matched subgroups, those on a generic went an average of 138 days before having a 14-day gap in treatment, compared with an average 124 days until a 14-day treatment gap occurred among those on a branded drug. This difference in adherence linked with a significant difference in seizure-related hospitalizations, experienced by 47 patients who started on a branded drug and in 31 of those who started on a generic. This calculated out to a statistically significant relative risk reduction of more than 50% (Epilepsy Behavior. 2015 Nov;52[part A]:14-8).
Often it is the physician that’s to blame when patients lack trust in a generic drug, noted Dr. Michel J. Berg, a neurologist at the University of Rochester (N.Y.) and coprincipal investigator on the two EQUIGEN studies. “If physicians are confident [in generics] then patients will rely on the physician’s expert opinion,” Dr. Berg said during a panel discussion of these studies during the session.
Patients and physicians also need to realize that today’s generics are often not the same products that they were years ago. The FDA has “encouraged manufacturers to move from ’quality by testing’ to ‘quality by design,’ which has resulted in better products,” stressed Dr. Jiang.
Dr. Privitera agreed. “A lot of the fear about generics was generated 20 or more years ago, when the generic quality was not as good. There were a lot of scary stories out there. Today, with quality by design, manufacturers don’t just try to get their generic in a target range but they do multiple tests earlier in the [generic development] process so that by the time they get to clinical testing they already have a drug that is really tight.”
Members of the audience at the session who commented during the discussion period usually agreed that the new data reported for lamotrigine convinced them of the quality of modern generics. “There has been discomfort with generics, but now we have the data that they are effective and safe,” commented Dr. Mark C. Spitz, professor of neurology and head of the Adult Comprehensive Epilepsy Program at the University of Colorado at Denver, Aurora, who spoke from the floor. “These new data will make a big difference in how epileptologists will practice,” Dr. Spitz predicted.
On Twitter @mitchelzoler
PHILADELPHIA – Several different generic lamotrigine products proved pharmacologically and clinically equivalent to Lamictal, the brand-name, reference form of lamotrigine, in three separate, prospective, randomized trials run by two independent groups. These results that should lay to rest lingering concerns by physicians and patients that generic lamotrigine poses any risk to patients, agreed a panel of experts speaking at a session at the annual meeting of the American Epilepsy Society.
The findings, which confirmed the standards now set by the Food and Drug Administration for deeming generic products equivalent to their reference product, should also reassure physicians and patients more broadly about the reliability of the generic forms of most other antiepileptic drugs as well as generic drugs used for virtually all indications across the range of medical practice, the panelists said.
The results of these three new studies “show that generic drugs have the same quality as the reference-listed drugs in patients with epilepsy,” said Dr. Wenlei Jiang, acting deputy director of the FDA’s Office of Research Standards and Office of Generic Drugs. Dr. Jiang coauthored one of the new studies.
“We were a skeptical group going into our studies,” said Dr. Michael Privitera, coprincipal investigator for the other two new studies. “We were not sure that these drugs [brand-name lamotrigine and various generic products] were really the same. We were shocked at how equivalent they were. It wasn’t that the differences [among their pharmacokinetic profiles] were small; it’s that there was no difference. We could not see any difference,” said Dr. Privitera, professor of neurology and director of the Epilepsy Center at the University of Cincinnati.
“We chose to study lamotrigine because there had been a lot of complaints [about the generic products] and because it is a drug that is very susceptible to drug-drug interactions. There is no reason I can think of why what we found would not extend to all antiepileptic drugs except for phenytoin, which has saturation kinetics and the way the FDA tests drugs in a single-dose study is not appropriate for drugs with saturation kinetics,” Dr. Privitera said in an interview. The implications of the new findings also extend beyond just drugs for epilepsy or other neurologic conditions, he added.
“When you have a very complicated disorder like epilepsy, which has the possibility for drug-drug interactions, and we could show this much quality” in the generic products, it has implications for the entire universe of generic drugs that show equivalence in FDA-mandated testing, Dr. Privitera said.
Randomized trials in epilepsy patients
One of the two studies run by Dr. Privitera and his associates used a single-dose format, and the second used a chronic-dosage format.
The EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy) Single Dose Study enrolled 48 epilepsy patients at any of six U.S. centers. All patients were on an antiepileptic drug other than lamotrigine, and the researchers randomized them to receive single doses of the brand-name reference form of lamotrigine (Lamictal), or either of two generic forms of lamotrigine. Patients received single dosages of each of the three study drugs with a 12-23 day washout period separating each dose (the preferred washout interval was 14 days), with the patients and researchers blinded to which specific product was administered at any time. The researchers selected the two FDA-approved generic products with the most widely divergent profiles based on in vitro dissolution testing and prior pharmacokinetic data supplied to the FDA. Forty-five patients received the scheduled two doses (on two different occasions) of each drug, a total of six test doses administered. The remaining three patients received a single dose of each of the three tested products.
All three products resulted in essentially superimposed concentration-time curves and area under the curve measures with no outliers or serious adverse events seen, Dr. Privitera and his associates reported in a poster presented at the meeting as well as during the session.
The EQUIGEN Chronic Dose Study compared the pharmacokinetic patterns after chronic dosing for 2 weeks with one of the two most disparate lamotrigine generic products. The study enrolled 35 patients with epilepsy at any of six U.S. centers, and 33 patients completed all four treatment periods, which involved a repeated crossover between the two study products. Patients received lamotrigine twice daily and could be on additional antiepileptic drugs or monotherapy; six patients received concomitant enzyme-inducing antiepileptic drugs during the study. The results showed that the area under the curve for both products had 90% confidence intervals of 98%-103%, compared with Lamictal, and they both had a 90% confidence interval for peak plasma concentration of 99%-105%, Dr. Privitera and his associates reported at the session. None of the enrolled patients showed unexpected adverse events, and the two generics produced similar adverse-event profiles.
The third study, BEEP (Bioequivalence in Epilepsy Patients) ran at the University of Maryland, Baltimore, and the results appeared in a journal article published in September (Epilepsia. 2015 Sept;56[9]:1415-24). This study enrolled 34 “generic brittle” epilepsy patients, which meant they had already shown signs of possible sensitivity to switching from Lamictal to generic lamotrigine. The study randomized patients to four consecutive 2-week periods of treatment with either the brand-name or a generic lamotrigine product in a crossover design that was then repeated, and each patient underwent a 12-hour pharmacokinetic analysis after they reached a steady-state drug level with 2 weeks of treatment. The results showed a tight match for both the area under the curve and peak plasma concentration for the generic and brand drugs, said Dr. Tricia Y. Ting, lead investigator for the study and a neurologist and epilepsy specialist at the University of Maryland Medical Center in Baltimore.
“The results could not have been more beautiful. We were quite surprised at how close the generic and brand products were” in their steady-state pharmacokinetic profiles, Dr. Ting said during the session.
The results of the three studies, while reassuring, raise questions as to why some patients nevertheless report problems while taking generic products, noted Dr. Ting. “We need to look outside of bioequivalence, and focus instead on issues such as patient expectations,” she said.
Patient factors
Dr. Joshua J. Gagne, a pharmacoepidemiologist at Brigham and Women’s Hospital in Boston, discussed the role of patient expectations and other patient-specific factors that can affect the safety and efficacy of generic products. He noted that patients can be confused by generic pills that do not have the same size, shape, or color as their brand-name counterparts. “Variations in appearance with generic antiepilepsy drugs is a real problem and may be a barrier to adherence,” he said. In addition, “patients’ out of pocket costs are important drivers of antiepileptic drug adherence,” and may act in favor of generics, he said.
He documented this potential effect in a recent study he published and also summarized while speaking during the session. Dr. Gagne and his associates used a database of more than 19,000 U.S. Medicare patients with epilepsy who began treatment with an antiepileptic drug. The researchers used propensity scoring to match a subset from among the 18,306 patients who started on a generic drug and the 1,454 patients who started on a brand-name drug. In the matched subgroups, those on a generic went an average of 138 days before having a 14-day gap in treatment, compared with an average 124 days until a 14-day treatment gap occurred among those on a branded drug. This difference in adherence linked with a significant difference in seizure-related hospitalizations, experienced by 47 patients who started on a branded drug and in 31 of those who started on a generic. This calculated out to a statistically significant relative risk reduction of more than 50% (Epilepsy Behavior. 2015 Nov;52[part A]:14-8).
Often it is the physician that’s to blame when patients lack trust in a generic drug, noted Dr. Michel J. Berg, a neurologist at the University of Rochester (N.Y.) and coprincipal investigator on the two EQUIGEN studies. “If physicians are confident [in generics] then patients will rely on the physician’s expert opinion,” Dr. Berg said during a panel discussion of these studies during the session.
Patients and physicians also need to realize that today’s generics are often not the same products that they were years ago. The FDA has “encouraged manufacturers to move from ’quality by testing’ to ‘quality by design,’ which has resulted in better products,” stressed Dr. Jiang.
Dr. Privitera agreed. “A lot of the fear about generics was generated 20 or more years ago, when the generic quality was not as good. There were a lot of scary stories out there. Today, with quality by design, manufacturers don’t just try to get their generic in a target range but they do multiple tests earlier in the [generic development] process so that by the time they get to clinical testing they already have a drug that is really tight.”
Members of the audience at the session who commented during the discussion period usually agreed that the new data reported for lamotrigine convinced them of the quality of modern generics. “There has been discomfort with generics, but now we have the data that they are effective and safe,” commented Dr. Mark C. Spitz, professor of neurology and head of the Adult Comprehensive Epilepsy Program at the University of Colorado at Denver, Aurora, who spoke from the floor. “These new data will make a big difference in how epileptologists will practice,” Dr. Spitz predicted.
On Twitter @mitchelzoler
PHILADELPHIA – Several different generic lamotrigine products proved pharmacologically and clinically equivalent to Lamictal, the brand-name, reference form of lamotrigine, in three separate, prospective, randomized trials run by two independent groups. These results that should lay to rest lingering concerns by physicians and patients that generic lamotrigine poses any risk to patients, agreed a panel of experts speaking at a session at the annual meeting of the American Epilepsy Society.
The findings, which confirmed the standards now set by the Food and Drug Administration for deeming generic products equivalent to their reference product, should also reassure physicians and patients more broadly about the reliability of the generic forms of most other antiepileptic drugs as well as generic drugs used for virtually all indications across the range of medical practice, the panelists said.
The results of these three new studies “show that generic drugs have the same quality as the reference-listed drugs in patients with epilepsy,” said Dr. Wenlei Jiang, acting deputy director of the FDA’s Office of Research Standards and Office of Generic Drugs. Dr. Jiang coauthored one of the new studies.
“We were a skeptical group going into our studies,” said Dr. Michael Privitera, coprincipal investigator for the other two new studies. “We were not sure that these drugs [brand-name lamotrigine and various generic products] were really the same. We were shocked at how equivalent they were. It wasn’t that the differences [among their pharmacokinetic profiles] were small; it’s that there was no difference. We could not see any difference,” said Dr. Privitera, professor of neurology and director of the Epilepsy Center at the University of Cincinnati.
“We chose to study lamotrigine because there had been a lot of complaints [about the generic products] and because it is a drug that is very susceptible to drug-drug interactions. There is no reason I can think of why what we found would not extend to all antiepileptic drugs except for phenytoin, which has saturation kinetics and the way the FDA tests drugs in a single-dose study is not appropriate for drugs with saturation kinetics,” Dr. Privitera said in an interview. The implications of the new findings also extend beyond just drugs for epilepsy or other neurologic conditions, he added.
“When you have a very complicated disorder like epilepsy, which has the possibility for drug-drug interactions, and we could show this much quality” in the generic products, it has implications for the entire universe of generic drugs that show equivalence in FDA-mandated testing, Dr. Privitera said.
Randomized trials in epilepsy patients
One of the two studies run by Dr. Privitera and his associates used a single-dose format, and the second used a chronic-dosage format.
The EQUIGEN (Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy) Single Dose Study enrolled 48 epilepsy patients at any of six U.S. centers. All patients were on an antiepileptic drug other than lamotrigine, and the researchers randomized them to receive single doses of the brand-name reference form of lamotrigine (Lamictal), or either of two generic forms of lamotrigine. Patients received single dosages of each of the three study drugs with a 12-23 day washout period separating each dose (the preferred washout interval was 14 days), with the patients and researchers blinded to which specific product was administered at any time. The researchers selected the two FDA-approved generic products with the most widely divergent profiles based on in vitro dissolution testing and prior pharmacokinetic data supplied to the FDA. Forty-five patients received the scheduled two doses (on two different occasions) of each drug, a total of six test doses administered. The remaining three patients received a single dose of each of the three tested products.
All three products resulted in essentially superimposed concentration-time curves and area under the curve measures with no outliers or serious adverse events seen, Dr. Privitera and his associates reported in a poster presented at the meeting as well as during the session.
The EQUIGEN Chronic Dose Study compared the pharmacokinetic patterns after chronic dosing for 2 weeks with one of the two most disparate lamotrigine generic products. The study enrolled 35 patients with epilepsy at any of six U.S. centers, and 33 patients completed all four treatment periods, which involved a repeated crossover between the two study products. Patients received lamotrigine twice daily and could be on additional antiepileptic drugs or monotherapy; six patients received concomitant enzyme-inducing antiepileptic drugs during the study. The results showed that the area under the curve for both products had 90% confidence intervals of 98%-103%, compared with Lamictal, and they both had a 90% confidence interval for peak plasma concentration of 99%-105%, Dr. Privitera and his associates reported at the session. None of the enrolled patients showed unexpected adverse events, and the two generics produced similar adverse-event profiles.
The third study, BEEP (Bioequivalence in Epilepsy Patients) ran at the University of Maryland, Baltimore, and the results appeared in a journal article published in September (Epilepsia. 2015 Sept;56[9]:1415-24). This study enrolled 34 “generic brittle” epilepsy patients, which meant they had already shown signs of possible sensitivity to switching from Lamictal to generic lamotrigine. The study randomized patients to four consecutive 2-week periods of treatment with either the brand-name or a generic lamotrigine product in a crossover design that was then repeated, and each patient underwent a 12-hour pharmacokinetic analysis after they reached a steady-state drug level with 2 weeks of treatment. The results showed a tight match for both the area under the curve and peak plasma concentration for the generic and brand drugs, said Dr. Tricia Y. Ting, lead investigator for the study and a neurologist and epilepsy specialist at the University of Maryland Medical Center in Baltimore.
“The results could not have been more beautiful. We were quite surprised at how close the generic and brand products were” in their steady-state pharmacokinetic profiles, Dr. Ting said during the session.
The results of the three studies, while reassuring, raise questions as to why some patients nevertheless report problems while taking generic products, noted Dr. Ting. “We need to look outside of bioequivalence, and focus instead on issues such as patient expectations,” she said.
Patient factors
Dr. Joshua J. Gagne, a pharmacoepidemiologist at Brigham and Women’s Hospital in Boston, discussed the role of patient expectations and other patient-specific factors that can affect the safety and efficacy of generic products. He noted that patients can be confused by generic pills that do not have the same size, shape, or color as their brand-name counterparts. “Variations in appearance with generic antiepilepsy drugs is a real problem and may be a barrier to adherence,” he said. In addition, “patients’ out of pocket costs are important drivers of antiepileptic drug adherence,” and may act in favor of generics, he said.
He documented this potential effect in a recent study he published and also summarized while speaking during the session. Dr. Gagne and his associates used a database of more than 19,000 U.S. Medicare patients with epilepsy who began treatment with an antiepileptic drug. The researchers used propensity scoring to match a subset from among the 18,306 patients who started on a generic drug and the 1,454 patients who started on a brand-name drug. In the matched subgroups, those on a generic went an average of 138 days before having a 14-day gap in treatment, compared with an average 124 days until a 14-day treatment gap occurred among those on a branded drug. This difference in adherence linked with a significant difference in seizure-related hospitalizations, experienced by 47 patients who started on a branded drug and in 31 of those who started on a generic. This calculated out to a statistically significant relative risk reduction of more than 50% (Epilepsy Behavior. 2015 Nov;52[part A]:14-8).
Often it is the physician that’s to blame when patients lack trust in a generic drug, noted Dr. Michel J. Berg, a neurologist at the University of Rochester (N.Y.) and coprincipal investigator on the two EQUIGEN studies. “If physicians are confident [in generics] then patients will rely on the physician’s expert opinion,” Dr. Berg said during a panel discussion of these studies during the session.
Patients and physicians also need to realize that today’s generics are often not the same products that they were years ago. The FDA has “encouraged manufacturers to move from ’quality by testing’ to ‘quality by design,’ which has resulted in better products,” stressed Dr. Jiang.
Dr. Privitera agreed. “A lot of the fear about generics was generated 20 or more years ago, when the generic quality was not as good. There were a lot of scary stories out there. Today, with quality by design, manufacturers don’t just try to get their generic in a target range but they do multiple tests earlier in the [generic development] process so that by the time they get to clinical testing they already have a drug that is really tight.”
Members of the audience at the session who commented during the discussion period usually agreed that the new data reported for lamotrigine convinced them of the quality of modern generics. “There has been discomfort with generics, but now we have the data that they are effective and safe,” commented Dr. Mark C. Spitz, professor of neurology and head of the Adult Comprehensive Epilepsy Program at the University of Colorado at Denver, Aurora, who spoke from the floor. “These new data will make a big difference in how epileptologists will practice,” Dr. Spitz predicted.
On Twitter @mitchelzoler
AT AES 2015
Key clinical point: Results from three separate, randomized trials in epilepsy patients showed that generic lamotrigine performed identically to brand-name Lamictal.
Major finding: During chronic treatment, generic lamotrigine produced an area under the curve within 98%-103% of the brand-name, reference product Lamictal.
Data source: The prospective, randomized U.S. trials that respectively enrolled 48, 35, and 34 epilepsy patients.
Disclosures: The two EQUIGEN studies and the BEEP study had no commercial funding. Dr. Jiang had no disclosures. Dr. Privitera has received research funding from UCB, Eisai, and Neuren Pharmaceuticals and has served on the data safety and monitoring boards for trials funded by Astellas and Upsher-Smith. Dr. Ting has received research funding from Acorda and Pfizer. Dr. Gagne has received research funding from Teva and Novartis and is a consultant to Aetion. Dr. Berg has received research funding from Eisai, NeuroPace, Sunovion, Pfizer, Lundbeck, and Acorda. He also is a stockholder in and has patent rights licensed to PharmAdva and Jemsico. Dr. Spitz has been a consultant to Cyberonics.
