Martin Berman-Gorvine

The Food and Drug Administration’s opinion that a progesterone gel 8% lacks statistically significant proof of efficacy in reducing preterm births among U.S. women with a short cervix, while stronger evidence in ex-U.S. populations is offset by the different racial makeup in the foreign sites, makes a difficult-to-surmount problem for the sponsor going into the Jan. 20 meeting of the Reproductive Health Drugs Advisory Committee.

The FDA reviewers also rejected the sponsor’s statistical analysis on a crucial point. The new drug application was based on a single pivotal phase III trial, "Study 302," a prospective randomized trial that enrolled women with a cervical length of 1-2 cm as measured by transvaginal ultrasound at 23 U.S. sites and 21 sites in nine foreign countries.

Columbia Laboratories Inc.’s progesterone gel 8% would be indicated for the reduction of risk of preterm birth in women with a singleton gestation and a short uterine cervical length in the midtrimester of pregnancy.

The 8% progesterone gel has been known by the proposed brand name Prochieve, but while the drug is marketed under that brand name for different indications in other countries, it is not cited as the brand name for the prevention of the preterm birth indication in Columbia’s background document.

Supporting evidence came from the earlier "Study 300," which had failed to find statistically significant evidence that progesterone worked in preventing preterm births in high-risk pregnant women but found evidence of efficacy in the subgroup of women with short cervixes. The sponsor and the FDA agreed on the design of Study 302 based on this latter result. The estimated user fee goal date for Columbia’s application is Feb. 26.

Columbia presented analyses based on pooled data from both studies, a Cochran Mantel Haenszel test stratified by primary pooled study site and risk strata, but the FDA said this was not statistically sound due to the differences in the study populations and initiation of treatment. Moreover, the supplemental information from Study 300 did not provide adequate efficacy evidence since the short cervix subgroups analyzed included too few subjects – 9-116 subjects in total, depending on the specific definition used for short cervix.

According to the FDA, a cervical length of 2.5 cm or less "is generally considered to represent a clinically meaningful short cervix and a risk factor for preterm birth; only 33 subjects in Study 300 fell into this range." At a July 2007 meeting between Columbia and the FDA’s Division of Reproductive and Urologic Products, following the failure of Study 300, the sponsor proposed defining a "short cervix" as less than 2.8 cm for what would become Study 302, and the division said that while the literature generally defines a short cervix as one measuring less than 2.5 cm, "a robust finding in a population at any prespecified shortened cervical length would be of clinical importance."

Lack of Evidence for U.S. Population

Most damagingly for Columbia, the FDA’s analyses indicate that progesterone gel was not associated with a reduction in preterm birth in the U.S. subjects at any gestational age, with a treatment difference of only 2.4% in favor of progesterone gel compared with placebo before 33 weeks’ gestation. Moreover, "the CI around this point estimate of the risk difference indicated that the difference is not statistically significant," the FDA says in a background document prepared for the advisory panel meeting. "In addition, the key secondary end point of neonatal mortality and morbidity did not show a statistically significant treatment effect of progesterone gel."

The FDA found the results were literally all over the map, with South Africa and Belarus having very high rates of preterm births in the placebo patients and none in the progesterone-treated group, a result not replicated elsewhere.

"The treatment effect also shows marked heterogeneity, even within the U.S., where the difference in the preterm birth rate in placebo-treated subjects compared to those treated with progesterone gel ranged from -12% (favoring progesterone gel) to +7% (favoring placebo)," the Division of Reproductive and Urologic Products noted. "Similarly, three large Indian sites showed pooled results that favored placebo by 9%, while other non-U.S. sites showed treatment effects favoring progesterone gel that ranged from -4% to -31%."

The racial makeup of the U.S. enrolled population in Study 302 also differed substantially from that enrolled outside the United States, which is bound to spell additional trouble for the application. The majority of U.S. subjects were black (60%) and white (29%), while the majority of subjects in non-U.S. sites were Asian (59%) and white (23%). According to the FDA, "The preterm birth rate in placebo-treated subjects varies considerably by race. This may also reflect regional differences, as race was differentially distributed by region. Overall, there was minimal efficacy in Asian subjects, possibly because the background rate of prematurity was quite low. Efficacy in [whites] and blacks favored progesterone gel. In [whites], the treatment benefit was greatest in the earlier gestational ages, while in blacks, efficacy increased as gestational age advanced."

Columbia’s background materials appeared to reflect a different universe of assumptions. "In the efficacy results from Study 302, the U.S. and non-U.S. regions both favored progesterone, although the size of the treatment effect was greater in the non-U.S. regions," the sponsor said. "In contrast, in Study 300 the results for the U.S. subgroup favored progesterone, whereas the non-U.S. results favored placebo. This finding supports the conclusion that the Study 302 regional effect can be attributed to normal variability among subgroups when considering an end point of low incidence; the totality of data from the program suggests beneficial treatment effects in the U.S."

The issues the FDA outlines for advisory committee discussion further indicate the agency’s skepticism about the product’s approvability:

• Has the Applicant provided sufficient information to conclude that progesterone gel reduces the risk of preterm birth in women with a singleton gestation and a short uterine cervical length at midtrimester of pregnancy, given that statistically significant efficacy was not demonstrated in U.S. subjects?

• Do you believe that there is any explanation, based on the data provided in the NDA, for the difference in efficacy results in the U.S. and foreign populations? If yes, do you believe that the explanation could be adequately addressed in labeling so that progesterone gel could be used safely and effectively in the U.S. population?

• Has the Applicant provided sufficient information to conclude that the safety profile for progesterone gel is acceptable for the proposed indication?

Is the overall risk/benefit profile of progesterone gel acceptable to support approval of this product in the U.S. for the proposed indication?

• If not, do you have recommendations as to how efficacy and/or safety could be investigated further in the U.S. population (e.g., a new study)?

Finally, the unmet medical need argument may not be persuasive here due to the approval on Feb. 4, 2011, of KV Pharmaceutical Co.’s Makena (alpha hydroxyprogesterone caproate, or 17P), a synthetic form of progestin given in weekly injections to eligible pregnant women between 16 and 20 weeks’ gestation and continuing until 37 weeks for prevention of preterm birth in women carrying only one fetus who have a history of spontaneous preterm birth with singleton pregnancies.

Makena has drawn the FDA’s ire after launch, however, and in a nod to political pressure regarding the product’s pricing, the agency has not been taking enforcement action against the compounding pharmacies that are still making unapproved versions of the drug at a fraction of the cost, even as KV marshals evidence of their substandard purity and potency.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s opinion that a progesterone gel 8% lacks statistically significant proof of efficacy in reducing preterm births among U.S. women with a short cervix, while stronger evidence in ex-U.S. populations is offset by the different racial makeup in the foreign sites, makes a difficult-to-surmount problem for the sponsor going into the Jan. 20 meeting of the Reproductive Health Drugs Advisory Committee.

The FDA reviewers also rejected the sponsor’s statistical analysis on a crucial point. The new drug application was based on a single pivotal phase III trial, "Study 302," a prospective randomized trial that enrolled women with a cervical length of 1-2 cm as measured by transvaginal ultrasound at 23 U.S. sites and 21 sites in nine foreign countries.

Columbia Laboratories Inc.’s progesterone gel 8% would be indicated for the reduction of risk of preterm birth in women with a singleton gestation and a short uterine cervical length in the midtrimester of pregnancy.

The 8% progesterone gel has been known by the proposed brand name Prochieve, but while the drug is marketed under that brand name for different indications in other countries, it is not cited as the brand name for the prevention of the preterm birth indication in Columbia’s background document.

Supporting evidence came from the earlier "Study 300," which had failed to find statistically significant evidence that progesterone worked in preventing preterm births in high-risk pregnant women but found evidence of efficacy in the subgroup of women with short cervixes. The sponsor and the FDA agreed on the design of Study 302 based on this latter result. The estimated user fee goal date for Columbia’s application is Feb. 26.

Columbia presented analyses based on pooled data from both studies, a Cochran Mantel Haenszel test stratified by primary pooled study site and risk strata, but the FDA said this was not statistically sound due to the differences in the study populations and initiation of treatment. Moreover, the supplemental information from Study 300 did not provide adequate efficacy evidence since the short cervix subgroups analyzed included too few subjects – 9-116 subjects in total, depending on the specific definition used for short cervix.

According to the FDA, a cervical length of 2.5 cm or less "is generally considered to represent a clinically meaningful short cervix and a risk factor for preterm birth; only 33 subjects in Study 300 fell into this range." At a July 2007 meeting between Columbia and the FDA’s Division of Reproductive and Urologic Products, following the failure of Study 300, the sponsor proposed defining a "short cervix" as less than 2.8 cm for what would become Study 302, and the division said that while the literature generally defines a short cervix as one measuring less than 2.5 cm, "a robust finding in a population at any prespecified shortened cervical length would be of clinical importance."

Lack of Evidence for U.S. Population

Most damagingly for Columbia, the FDA’s analyses indicate that progesterone gel was not associated with a reduction in preterm birth in the U.S. subjects at any gestational age, with a treatment difference of only 2.4% in favor of progesterone gel compared with placebo before 33 weeks’ gestation. Moreover, "the CI around this point estimate of the risk difference indicated that the difference is not statistically significant," the FDA says in a background document prepared for the advisory panel meeting. "In addition, the key secondary end point of neonatal mortality and morbidity did not show a statistically significant treatment effect of progesterone gel."

The FDA found the results were literally all over the map, with South Africa and Belarus having very high rates of preterm births in the placebo patients and none in the progesterone-treated group, a result not replicated elsewhere.

"The treatment effect also shows marked heterogeneity, even within the U.S., where the difference in the preterm birth rate in placebo-treated subjects compared to those treated with progesterone gel ranged from -12% (favoring progesterone gel) to +7% (favoring placebo)," the Division of Reproductive and Urologic Products noted. "Similarly, three large Indian sites showed pooled results that favored placebo by 9%, while other non-U.S. sites showed treatment effects favoring progesterone gel that ranged from -4% to -31%."

The racial makeup of the U.S. enrolled population in Study 302 also differed substantially from that enrolled outside the United States, which is bound to spell additional trouble for the application. The majority of U.S. subjects were black (60%) and white (29%), while the majority of subjects in non-U.S. sites were Asian (59%) and white (23%). According to the FDA, "The preterm birth rate in placebo-treated subjects varies considerably by race. This may also reflect regional differences, as race was differentially distributed by region. Overall, there was minimal efficacy in Asian subjects, possibly because the background rate of prematurity was quite low. Efficacy in [whites] and blacks favored progesterone gel. In [whites], the treatment benefit was greatest in the earlier gestational ages, while in blacks, efficacy increased as gestational age advanced."

Columbia’s background materials appeared to reflect a different universe of assumptions. "In the efficacy results from Study 302, the U.S. and non-U.S. regions both favored progesterone, although the size of the treatment effect was greater in the non-U.S. regions," the sponsor said. "In contrast, in Study 300 the results for the U.S. subgroup favored progesterone, whereas the non-U.S. results favored placebo. This finding supports the conclusion that the Study 302 regional effect can be attributed to normal variability among subgroups when considering an end point of low incidence; the totality of data from the program suggests beneficial treatment effects in the U.S."

The issues the FDA outlines for advisory committee discussion further indicate the agency’s skepticism about the product’s approvability:

• Has the Applicant provided sufficient information to conclude that progesterone gel reduces the risk of preterm birth in women with a singleton gestation and a short uterine cervical length at midtrimester of pregnancy, given that statistically significant efficacy was not demonstrated in U.S. subjects?

• Do you believe that there is any explanation, based on the data provided in the NDA, for the difference in efficacy results in the U.S. and foreign populations? If yes, do you believe that the explanation could be adequately addressed in labeling so that progesterone gel could be used safely and effectively in the U.S. population?

• Has the Applicant provided sufficient information to conclude that the safety profile for progesterone gel is acceptable for the proposed indication?

Is the overall risk/benefit profile of progesterone gel acceptable to support approval of this product in the U.S. for the proposed indication?

• If not, do you have recommendations as to how efficacy and/or safety could be investigated further in the U.S. population (e.g., a new study)?

Finally, the unmet medical need argument may not be persuasive here due to the approval on Feb. 4, 2011, of KV Pharmaceutical Co.’s Makena (alpha hydroxyprogesterone caproate, or 17P), a synthetic form of progestin given in weekly injections to eligible pregnant women between 16 and 20 weeks’ gestation and continuing until 37 weeks for prevention of preterm birth in women carrying only one fetus who have a history of spontaneous preterm birth with singleton pregnancies.

Makena has drawn the FDA’s ire after launch, however, and in a nod to political pressure regarding the product’s pricing, the agency has not been taking enforcement action against the compounding pharmacies that are still making unapproved versions of the drug at a fraction of the cost, even as KV marshals evidence of their substandard purity and potency.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration’s opinion that a progesterone gel 8% lacks statistically significant proof of efficacy in reducing preterm births among U.S. women with a short cervix, while stronger evidence in ex-U.S. populations is offset by the different racial makeup in the foreign sites, makes a difficult-to-surmount problem for the sponsor going into the Jan. 20 meeting of the Reproductive Health Drugs Advisory Committee.

The FDA reviewers also rejected the sponsor’s statistical analysis on a crucial point. The new drug application was based on a single pivotal phase III trial, "Study 302," a prospective randomized trial that enrolled women with a cervical length of 1-2 cm as measured by transvaginal ultrasound at 23 U.S. sites and 21 sites in nine foreign countries.

Columbia Laboratories Inc.’s progesterone gel 8% would be indicated for the reduction of risk of preterm birth in women with a singleton gestation and a short uterine cervical length in the midtrimester of pregnancy.

The 8% progesterone gel has been known by the proposed brand name Prochieve, but while the drug is marketed under that brand name for different indications in other countries, it is not cited as the brand name for the prevention of the preterm birth indication in Columbia’s background document.

Supporting evidence came from the earlier "Study 300," which had failed to find statistically significant evidence that progesterone worked in preventing preterm births in high-risk pregnant women but found evidence of efficacy in the subgroup of women with short cervixes. The sponsor and the FDA agreed on the design of Study 302 based on this latter result. The estimated user fee goal date for Columbia’s application is Feb. 26.

Columbia presented analyses based on pooled data from both studies, a Cochran Mantel Haenszel test stratified by primary pooled study site and risk strata, but the FDA said this was not statistically sound due to the differences in the study populations and initiation of treatment. Moreover, the supplemental information from Study 300 did not provide adequate efficacy evidence since the short cervix subgroups analyzed included too few subjects – 9-116 subjects in total, depending on the specific definition used for short cervix.

According to the FDA, a cervical length of 2.5 cm or less "is generally considered to represent a clinically meaningful short cervix and a risk factor for preterm birth; only 33 subjects in Study 300 fell into this range." At a July 2007 meeting between Columbia and the FDA’s Division of Reproductive and Urologic Products, following the failure of Study 300, the sponsor proposed defining a "short cervix" as less than 2.8 cm for what would become Study 302, and the division said that while the literature generally defines a short cervix as one measuring less than 2.5 cm, "a robust finding in a population at any prespecified shortened cervical length would be of clinical importance."

Lack of Evidence for U.S. Population

Most damagingly for Columbia, the FDA’s analyses indicate that progesterone gel was not associated with a reduction in preterm birth in the U.S. subjects at any gestational age, with a treatment difference of only 2.4% in favor of progesterone gel compared with placebo before 33 weeks’ gestation. Moreover, "the CI around this point estimate of the risk difference indicated that the difference is not statistically significant," the FDA says in a background document prepared for the advisory panel meeting. "In addition, the key secondary end point of neonatal mortality and morbidity did not show a statistically significant treatment effect of progesterone gel."

The FDA found the results were literally all over the map, with South Africa and Belarus having very high rates of preterm births in the placebo patients and none in the progesterone-treated group, a result not replicated elsewhere.

"The treatment effect also shows marked heterogeneity, even within the U.S., where the difference in the preterm birth rate in placebo-treated subjects compared to those treated with progesterone gel ranged from -12% (favoring progesterone gel) to +7% (favoring placebo)," the Division of Reproductive and Urologic Products noted. "Similarly, three large Indian sites showed pooled results that favored placebo by 9%, while other non-U.S. sites showed treatment effects favoring progesterone gel that ranged from -4% to -31%."

The racial makeup of the U.S. enrolled population in Study 302 also differed substantially from that enrolled outside the United States, which is bound to spell additional trouble for the application. The majority of U.S. subjects were black (60%) and white (29%), while the majority of subjects in non-U.S. sites were Asian (59%) and white (23%). According to the FDA, "The preterm birth rate in placebo-treated subjects varies considerably by race. This may also reflect regional differences, as race was differentially distributed by region. Overall, there was minimal efficacy in Asian subjects, possibly because the background rate of prematurity was quite low. Efficacy in [whites] and blacks favored progesterone gel. In [whites], the treatment benefit was greatest in the earlier gestational ages, while in blacks, efficacy increased as gestational age advanced."

Columbia’s background materials appeared to reflect a different universe of assumptions. "In the efficacy results from Study 302, the U.S. and non-U.S. regions both favored progesterone, although the size of the treatment effect was greater in the non-U.S. regions," the sponsor said. "In contrast, in Study 300 the results for the U.S. subgroup favored progesterone, whereas the non-U.S. results favored placebo. This finding supports the conclusion that the Study 302 regional effect can be attributed to normal variability among subgroups when considering an end point of low incidence; the totality of data from the program suggests beneficial treatment effects in the U.S."

The issues the FDA outlines for advisory committee discussion further indicate the agency’s skepticism about the product’s approvability:

• Has the Applicant provided sufficient information to conclude that progesterone gel reduces the risk of preterm birth in women with a singleton gestation and a short uterine cervical length at midtrimester of pregnancy, given that statistically significant efficacy was not demonstrated in U.S. subjects?

• Do you believe that there is any explanation, based on the data provided in the NDA, for the difference in efficacy results in the U.S. and foreign populations? If yes, do you believe that the explanation could be adequately addressed in labeling so that progesterone gel could be used safely and effectively in the U.S. population?

• Has the Applicant provided sufficient information to conclude that the safety profile for progesterone gel is acceptable for the proposed indication?

Is the overall risk/benefit profile of progesterone gel acceptable to support approval of this product in the U.S. for the proposed indication?

• If not, do you have recommendations as to how efficacy and/or safety could be investigated further in the U.S. population (e.g., a new study)?

Finally, the unmet medical need argument may not be persuasive here due to the approval on Feb. 4, 2011, of KV Pharmaceutical Co.’s Makena (alpha hydroxyprogesterone caproate, or 17P), a synthetic form of progestin given in weekly injections to eligible pregnant women between 16 and 20 weeks’ gestation and continuing until 37 weeks for prevention of preterm birth in women carrying only one fetus who have a history of spontaneous preterm birth with singleton pregnancies.

Makena has drawn the FDA’s ire after launch, however, and in a nod to political pressure regarding the product’s pricing, the agency has not been taking enforcement action against the compounding pharmacies that are still making unapproved versions of the drug at a fraction of the cost, even as KV marshals evidence of their substandard purity and potency.

This coverage is provided courtesy of "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

Food and Drug Administration officials disagree over whether the long-term use of oral bisphosphonates increases the risk of esophageal cancer, background documents released before an advisory committee meeting show.

The FDA added the question of whether long-term use of the drugs increases the risk of esophageal cancer to the agenda of the Sept. 9 joint session of the Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committees only after the agency had already scheduled the meeting.

None of the four approved drugs in this class – Merck’s Fosamax (alendronate), Warner Chilcott’s Actonel (risedronate), Novartis’ Reclast (zoledronic acid), and Roche’s Boniva (ibandronate) – currently carries any warning about an esophageal cancer risk, though the labels do warn of the risks of esophagitis and esophageal ulcers.

In reviews attached to the background documents, Judy Staffa, Ph.D., director of the FDA’s Division of Epidemiology II, expressed greater concern about the increased cancer risk with long-term use than did Dr. Stephen Voss, a medical reviewer in the agency’s Division of Reproductive and Urologic Products.

Dr. Staffa discussed two studies that used the General Practice Research Database as their data source. One of the studies used a retrospective cohort design (Cardwell et al. JAMA 2010;304:657-63), and the other used a nested case-control design (Green et al. BMJ 2010 Sept. 1 [doi:10.1136/bmj.c4444]).

While Dr. Staffa acknowledged that "definitive conclusions about the risk of esophageal cancer associated with the use of OBPs [oral bisphosphonates] cannot be made based on these two published studies alone," she said that "the signal generated by the Green study concerns me, and I am not reassured by the negative findings of the Cardwell study."

Therefore, Dr. Staffa said, "enough evidence exists to support adding this information to product labeling and issuing a drug safety communication to alert practitioners and patients to this signal, and the accompanying uncertainty, to let them know that we continue to investigate it."

That stands in contradiction to Dr. Voss’ view. "Although studies are conflicting, it is very clear that there is not a marked increase in esophageal cancer risk with oral BPs," he wrote.

"The evidence at this time does not appear to warrant any changes to BP prescribing or any other aspects of care in any subgroup of patients; thus, it is unclear what benefit may derive from increased awareness of the issue," he wrote.

The FDA listed two other possible risks of long-term BP use for preventing or treating osteoporosis that it wants the advisory committees to discuss: increased risk of developing osteonecrosis of the jaw (ONJ) and increased risk of atypical fractures.

The agency will ask the panels whether restricting duration of use, implementing a "drug holiday," or requiring label changes could help osteoporosis patients who require chronic long-term therapy. Dr. Theresa Kehoe of the FDA’s Division of Reproductive and Urologic Products raised the possibility of drug holidays in a conference call with reporters last October.

Evidence is cloudy on all these points, with existing studies having confounding factors, different definitions of atypical fractures, and very small numbers for ONJ.

For example, the FDA contracted with Kaiser Permanente of Northern California to conduct the "Predicting Risk of Osteonecrosis with Bisphosphonate Exposure" (PROBE) study, which found only nine cases of stage 1 or 2 ONJ among 8,572 patients who had taken OBPs for at least 1 year and responded to a mail survey. Of the nine cases, however, seven were in patients who had taken the drugs for more than 4 years.

Perhaps unsurprisingly, the drugs’ sponsors all touted the benefits of long-term oral BP use, especially for bone mineral density, and opposed label changes.

Merck and Novartis said that drug holidays could be implemented on an individual patient basis, but Warner Chilcott warned that any drug holiday could lead to "a compromised clinical benefit."

This coverage is provided by "The Pink Sheet." This news organization and "The Pink Sheet" are owned by Elsevier.

The Food and Drug Administration is looking to its Oncologic Drugs Advisory Committee for help in reconciling the fact that the results of the two pivotal phase III trials of Novartis’s Afinitor (everolimus) for neuroendocrine tumors do not support each other.

The supplemental application coming up for review on April 12 would cover advanced neuroendocrine tumors of gastrointestinal, lung, or pancreatic origin, and is based on two trials, one in pancreatic neuroendocrine tumors (PNET) and one in carcinoid tumors.

In a briefing document for the advisory committee meeting, the FDA highlights the inability of the two trials to support each other as one of four review issues. The impact of informative censoring on both studies, the effect of Afinitor on overall survival, and the use of progression-free survival (PFS) to establish clinical benefit and its impact on overall survival were also flagged as issues.

The FDA was troubled by a midstream change in primary end points in both trials. The original primary end point for both trials, which were designed and approved by the FDA under a Special Protocol Assessment, was PFS as determined by an independent radiology committee. However, in October 2009 Novartis and the FDA met to discuss "discordant evaluations of PFS by the local investigator and the IRC in the carcinoid study during the second interim analysis," the FDA’s briefing document says.

The primary end point of both trials was changed as a result – to PFS as determined by the local investigator in the PNET study, and to PFS as determined by a central adjudication committee in the carcinoid tumor study. At a pre-NDA meeting in August 2010, "FDA noted that both SPA agreements had been invalidated by this change in the primary end point and that the acceptability of the revised statistical plans would be a review issue," the agency said.

Discordant Results, Too

In the end, the results of the two trials were discordant, likely because of the discrepancies in efficacy assessments.

The PNET trial’s primary analysis indicated a statistically significant advantage in median PFS for patients taking Afinitor compared with those on placebo: 11.0 months vs. 4.6 months, per the investigator analysis.

In the primary analysis of the carcinoid tumor trial, based on the central adjudication committee, median PFS was 16.4 months for those taking the drug and 11.3 months for those taking the placebo, but it was not a statistically significant difference. According to Novartis, however, "everolimus, in combination with depot octreotide, has provided benefit for this population, despite the study not meeting its primary end point.

"Informative censoring proved to be a critical methodological challenge," Novartis added, asserting that secondary inverse probability of censoring weights analyses that corrected for this bias "provide evidence for a treatment effect." Censoring occurred in the trials when there was a dispute between the investigators and the radiology committee; the FDA briefing documents cite an example in which an investigator determined a patient to be suffering from progressive disease at cycle 7, while the radiology committee disagreed and censored the patient.

Overall survival (OS) is likely to pose another headache for Novartis, since neither trial demonstrated a benefit for patients taking Afinitor in this area. Both trials used a crossover design, allowing patients who progressed while on placebo to switch to the active arm. In the PNET trial, that ended up happening to 73% of the 203 placebo patients, according to an article in the Feb. 10 issue of the New England Journal of Medicine. The result was to confound the detection of a treatment-related survival benefit, the authors noted.

Novartis’s briefing document also notes that the crossover design in the carcinoid trial made it impossible to determine any OS benefit.

In fact, more patients on Afinitor died in this trial (100, or 46.3% of those in the active arm, compared with 85, or 39.9%, of those on placebo). In the PNET trial, 51 patients, or 24.6% of those in the active arm, died, compared with 50 of those on placebo, also constituting 24.6%. Both results were interim analyses; not enough events have occurred yet in either trial for a final analysis of OS.

This could be an especially big problem for Novartis given that the FDA’s enthusiasm for PFS end points for oncology drugs has been waning.

Afinitor is a multikinase inhibitor that forms an inhibitory complex with the mammalian target of rapamycin (mTOR). It is currently indicated for advanced renal cell carcinoma in patients who have received prior treatment with Pfizer’s Sutent (sunitinib) or Bayer’s Nexavar (sorafenib), for subependymal giant cell astrocytoma, and, under the trade name Zortress, for prophylaxis of kidney transplant rejection.

This coverage is provided courtesy of "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are both owned by Elsevier.

The Food and Drug Administration is looking to its Oncologic Drugs Advisory Committee for help in reconciling the fact that the results of the two pivotal phase III trials of Novartis’s Afinitor (everolimus) for neuroendocrine tumors do not support each other.

The supplemental application coming up for review on April 12 would cover advanced neuroendocrine tumors of gastrointestinal, lung, or pancreatic origin, and is based on two trials, one in pancreatic neuroendocrine tumors (PNET) and one in carcinoid tumors.

In a briefing document for the advisory committee meeting, the FDA highlights the inability of the two trials to support each other as one of four review issues. The impact of informative censoring on both studies, the effect of Afinitor on overall survival, and the use of progression-free survival (PFS) to establish clinical benefit and its impact on overall survival were also flagged as issues.

The FDA was troubled by a midstream change in primary end points in both trials. The original primary end point for both trials, which were designed and approved by the FDA under a Special Protocol Assessment, was PFS as determined by an independent radiology committee. However, in October 2009 Novartis and the FDA met to discuss "discordant evaluations of PFS by the local investigator and the IRC in the carcinoid study during the second interim analysis," the FDA’s briefing document says.

The primary end point of both trials was changed as a result – to PFS as determined by the local investigator in the PNET study, and to PFS as determined by a central adjudication committee in the carcinoid tumor study. At a pre-NDA meeting in August 2010, "FDA noted that both SPA agreements had been invalidated by this change in the primary end point and that the acceptability of the revised statistical plans would be a review issue," the agency said.

Discordant Results, Too

In the end, the results of the two trials were discordant, likely because of the discrepancies in efficacy assessments.

The PNET trial’s primary analysis indicated a statistically significant advantage in median PFS for patients taking Afinitor compared with those on placebo: 11.0 months vs. 4.6 months, per the investigator analysis.

In the primary analysis of the carcinoid tumor trial, based on the central adjudication committee, median PFS was 16.4 months for those taking the drug and 11.3 months for those taking the placebo, but it was not a statistically significant difference. According to Novartis, however, "everolimus, in combination with depot octreotide, has provided benefit for this population, despite the study not meeting its primary end point.

"Informative censoring proved to be a critical methodological challenge," Novartis added, asserting that secondary inverse probability of censoring weights analyses that corrected for this bias "provide evidence for a treatment effect." Censoring occurred in the trials when there was a dispute between the investigators and the radiology committee; the FDA briefing documents cite an example in which an investigator determined a patient to be suffering from progressive disease at cycle 7, while the radiology committee disagreed and censored the patient.

Overall survival (OS) is likely to pose another headache for Novartis, since neither trial demonstrated a benefit for patients taking Afinitor in this area. Both trials used a crossover design, allowing patients who progressed while on placebo to switch to the active arm. In the PNET trial, that ended up happening to 73% of the 203 placebo patients, according to an article in the Feb. 10 issue of the New England Journal of Medicine. The result was to confound the detection of a treatment-related survival benefit, the authors noted.

Novartis’s briefing document also notes that the crossover design in the carcinoid trial made it impossible to determine any OS benefit.

In fact, more patients on Afinitor died in this trial (100, or 46.3% of those in the active arm, compared with 85, or 39.9%, of those on placebo). In the PNET trial, 51 patients, or 24.6% of those in the active arm, died, compared with 50 of those on placebo, also constituting 24.6%. Both results were interim analyses; not enough events have occurred yet in either trial for a final analysis of OS.

This could be an especially big problem for Novartis given that the FDA’s enthusiasm for PFS end points for oncology drugs has been waning.

Afinitor is a multikinase inhibitor that forms an inhibitory complex with the mammalian target of rapamycin (mTOR). It is currently indicated for advanced renal cell carcinoma in patients who have received prior treatment with Pfizer’s Sutent (sunitinib) or Bayer’s Nexavar (sorafenib), for subependymal giant cell astrocytoma, and, under the trade name Zortress, for prophylaxis of kidney transplant rejection.

This coverage is provided courtesy of "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are both owned by Elsevier.

The Food and Drug Administration is looking to its Oncologic Drugs Advisory Committee for help in reconciling the fact that the results of the two pivotal phase III trials of Novartis’s Afinitor (everolimus) for neuroendocrine tumors do not support each other.

The supplemental application coming up for review on April 12 would cover advanced neuroendocrine tumors of gastrointestinal, lung, or pancreatic origin, and is based on two trials, one in pancreatic neuroendocrine tumors (PNET) and one in carcinoid tumors.

In a briefing document for the advisory committee meeting, the FDA highlights the inability of the two trials to support each other as one of four review issues. The impact of informative censoring on both studies, the effect of Afinitor on overall survival, and the use of progression-free survival (PFS) to establish clinical benefit and its impact on overall survival were also flagged as issues.

The FDA was troubled by a midstream change in primary end points in both trials. The original primary end point for both trials, which were designed and approved by the FDA under a Special Protocol Assessment, was PFS as determined by an independent radiology committee. However, in October 2009 Novartis and the FDA met to discuss "discordant evaluations of PFS by the local investigator and the IRC in the carcinoid study during the second interim analysis," the FDA’s briefing document says.

The primary end point of both trials was changed as a result – to PFS as determined by the local investigator in the PNET study, and to PFS as determined by a central adjudication committee in the carcinoid tumor study. At a pre-NDA meeting in August 2010, "FDA noted that both SPA agreements had been invalidated by this change in the primary end point and that the acceptability of the revised statistical plans would be a review issue," the agency said.

Discordant Results, Too

In the end, the results of the two trials were discordant, likely because of the discrepancies in efficacy assessments.

The PNET trial’s primary analysis indicated a statistically significant advantage in median PFS for patients taking Afinitor compared with those on placebo: 11.0 months vs. 4.6 months, per the investigator analysis.

In the primary analysis of the carcinoid tumor trial, based on the central adjudication committee, median PFS was 16.4 months for those taking the drug and 11.3 months for those taking the placebo, but it was not a statistically significant difference. According to Novartis, however, "everolimus, in combination with depot octreotide, has provided benefit for this population, despite the study not meeting its primary end point.

"Informative censoring proved to be a critical methodological challenge," Novartis added, asserting that secondary inverse probability of censoring weights analyses that corrected for this bias "provide evidence for a treatment effect." Censoring occurred in the trials when there was a dispute between the investigators and the radiology committee; the FDA briefing documents cite an example in which an investigator determined a patient to be suffering from progressive disease at cycle 7, while the radiology committee disagreed and censored the patient.

Overall survival (OS) is likely to pose another headache for Novartis, since neither trial demonstrated a benefit for patients taking Afinitor in this area. Both trials used a crossover design, allowing patients who progressed while on placebo to switch to the active arm. In the PNET trial, that ended up happening to 73% of the 203 placebo patients, according to an article in the Feb. 10 issue of the New England Journal of Medicine. The result was to confound the detection of a treatment-related survival benefit, the authors noted.

Novartis’s briefing document also notes that the crossover design in the carcinoid trial made it impossible to determine any OS benefit.

In fact, more patients on Afinitor died in this trial (100, or 46.3% of those in the active arm, compared with 85, or 39.9%, of those on placebo). In the PNET trial, 51 patients, or 24.6% of those in the active arm, died, compared with 50 of those on placebo, also constituting 24.6%. Both results were interim analyses; not enough events have occurred yet in either trial for a final analysis of OS.

This could be an especially big problem for Novartis given that the FDA’s enthusiasm for PFS end points for oncology drugs has been waning.

Afinitor is a multikinase inhibitor that forms an inhibitory complex with the mammalian target of rapamycin (mTOR). It is currently indicated for advanced renal cell carcinoma in patients who have received prior treatment with Pfizer’s Sutent (sunitinib) or Bayer’s Nexavar (sorafenib), for subependymal giant cell astrocytoma, and, under the trade name Zortress, for prophylaxis of kidney transplant rejection.

This coverage is provided courtesy of "The Pink Sheet." Internal Medicine News Digital Network and "The Pink Sheet" are both owned by Elsevier.

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

While an advisory committee will weigh design of the clinical program for an investigational aspirin substitute for heart bypass patients, a Food and Drug Administration official says a noninferiority trial may not be adequate.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will likely deliberate on the required size of a clinical study for Portola Pharmaceuticals’ drug PRT061103 when the panel reviews the product on Dec. 8.

Portola would like to use 64-slice computed tomography scans as a measure of "graft patency" – the degree to which the veins transplanted from a coronary artery bypass surgery patient’s arms or legs remain open following the operation, which in turn the company wishes to use as a surrogate end point for the efficacy of PRT061103, which is about to enter the clinic. The compound is meant to prevent cardiovascular problems in bypass patients who cannot take aspirin due to severe adverse reactions in their gastrointestinal lining.

But there are two major problems with this proposed study design, FDA Division of Cardiovascular and Renal Products Director Norman Stockbridge wrote in a briefing document for the upcoming committee meeting.

The company itself admits that the CT scans have lower sensitivity and specificity than invasive coronary angiography, which, however, carries risks of infrequent but major complications including stroke or death.

"As long as what is contemplated is a difference-finding study, I would have no issue with the loss of discriminatory power; it simply means that the trial needs to be a little larger to make up for missed or misclassified events," Dr. Stockbridge wrote. "How to compensate for this in a noninferiority trial is more complicated, as these features of CT make the two groups tend to look more similar."

Portola declined to comment on whether it is planning a noninferiority study of PRT061103 versus aspirin, citing the imminence of the advisory committee meeting.

CT Sensitivity Also Is a Worry

An even bigger problem with the company’s plans than the CT sensitivity issue is the usefulness of saphenous vein graft patency as a surrogate end point. The "FDA has questioned the adequacy of SVG patency as a surrogate (how likely it is to predict CV events)," Dr. Stockbridge wrote.

That’s because of a confounding effect in the supporting data Portola cites in its background package. The company uses data from the Coronary Artery Surgery Study Registry, a database of 24,959 patients from 1974-1979 at 15 centers across North America, to show that they had a better chance of survival if they had all three vessels bypassed.

"However, this is, of course, not a randomized comparison," Dr. Stockbridge said. "There is a reason relating to the patient’s underlying disease why all three vessels were not amenable to treatment, and these factors may well be responsible for poor outcome." The same applies to Portola’s attempt to show the same thing regarding reduction in the risk bypass recipients ran of contracting angina, the FDA reviewer added.

So while bypass surgery is itself an undoubted good, and the degree to which the grafts remain open may have something to do with the risks that patients will later have a heart attack or angina – which may seem intuitively obvious – "the strength of that relationship is not very strong," Dr. Stockbridge said.

Beyond PRT061103

The advisory committee’s recommendations may have implications for future product sponsors as well, since the stated purpose of the first part of the advisory panel’s deliberations is a general discussion of how to study thromboxane receptor antagonists such as PRT061103 for prevention of cardiovascular adverse events in CABG patients. The afternoon session will focus more specifically on Portola’s planned trial and will be closed to the public.

PRT061103 has completed preclinical studies, and Portola expects to start the phase I trial very soon. The firm also has more advanced anti-thrombotic candidate drugs in its pipeline – elinogrel and betrixaban, both of which have completed phase II studies.

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

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

For the sponsors of two benign prostatic hyperplasia drugs – Avodart (dutasteride) and Proscar (finasteride) – the task is to convince the Food and Drug Administration, an advisory panel, and ultimately physicians and patients that reduction in the risk of low-grade prostate cancer using their products is desirable. At the moment, the companies are trying to do it without mortality data.

Avodart-maker GlaxoSmithKline has filed a supplemental new drug application (sNDA) for an indication of reduction in prostate cancer risk (which would be a first in the United States), but Merck & Co. is not explicitly seeking such a claim for Proscar. However, Merck is seeking permission to include the results of the Prostate Cancer Prevention Trial (PCPT) of Proscar in the drug’s label.

"The proposed changes could be interpreted to suggest that Proscar is safe and effective for the prevention of prostate cancer in healthy men," the FDA noted in background materials prepared for the Dec. 1 meeting of the Oncologic Drugs Advisory Committee.

Both drugs are 5-alpha reductase inhibitors, and their similarities extend beyond their class to include design features of the pivotal studies they are using to prove their case – PCPT for Proscar and REDUCE for Avodart – that the agency finds questionable.

"Neither trial was adequately designed and conducted to characterize the ultimate outcomes of interest, specifically whether 5-alpha reductase treatment decreases the incidence of metastatic prostate cancer, prostate cancer–specific mortality or overall mortality," the FDA argued.

"In both trials, there was also an unexpected finding of an increased incidence of high-risk prostate cancers among men receiving 5-alpha reductase inhibitors," the agency said, adding that it is not convinced by the sponsors’ explanations of this finding that the risk isn’t real.

Are The Benefits – and the Biopsies – Worthwhile?

The FDA argued in similar terms for both Proscar and Avodart that the increase in high Gleason score prostate cancers seen among those treated with the drugs – that is, more aggressive cancers with a poorer prognosis – calls into question whether the risk reduction for lower-grade cancers is worth while. The sponsors argued that their drugs reduced prostate volumes, which may have made the high-risk cancers easier to detect.

More critically yet, that benefit is itself a questionable one, the FDA suggested, because it was established using procedures not followed in the practice of medicine and the results offer limited clinical guidance for patients and practitioners.

For Proscar, "the primary efficacy results for the PCPT are driven by ‘end of study’ biopsies and therefore raise questions regarding the applicability of the results to the current standard of care for the management of healthy middle-aged and elderly men with no clinical evidence of prostate cancer," the agency argued.

Similarly, the agency said, the results of the REDUCE (Reduction by Dutasteride of Prostate Cancer Events) trial of Avodart are of "questionable relevance ... to clinical practice, where only ‘for-cause biopsies’ are performed. The high prevalence of latent prostate cancer at autopsy (30%-70%) in men 50-80 years of age makes time-mandated, repeated biopsies without a clinical indication [as were done in both the PCPT and REDUCE studies] of questionable relevance."

As an FDA reviewer noted with regard to the REDUCE trial, "It is apparent that if men are biopsied frequently without cause, a high incidence of latent low-risk prostate cancers will be detected, most of which pose little threat to men during their lifetime. A decrease in incidence of these latent cancers is of limited value to patients."

The agency also criticized the low rate at which African American men, who are at heightened risk of prostate cancer, enrolled in the studies, constituting 4% of the PCPT trial population and 2% of REDUCE.

Sponsors Say Results Will Offer Patients Options

The trials did differ in enrollment criteria, length, and precise results. PCPT enrolled 18,882 men aged 55 and up with normal digital rectal examinations and prostate-specific antigen levels less than or equal to 3 mg/mL at study entry, with men at higher risk for developing prostate cancer being excluded. Equal numbers of participants were randomized to 5 mg of Proscar per day or placebo, with treatment continuing for 7 years or until diagnosis with prostate cancer. The cumulative incidence of prostate cancer was 18.4% in the active arm and 24.9% in the placebo arm.

In the REDUCE trial, 8,231 men at heightened risk of prostate cancer were randomized to 0.5 mg of Avodart daily or placebo for 4 years or until diagnosis of prostate cancer. Participants underwent transrectal ultrasound-guided biopsies at 2 and 4 years after enrollment. Men in the active arm enjoyed a 23% lower risk of being diagnosed with biopsy-detectable prostate cancer than did men on placebo.

For the sponsors, these results are worthwhile. The data from the PCPT trial "suggest that administration of finasteride to men at risk of prostate cancer significantly reduces the risk of the disease, thereby reducing the side effects and complications that accompany diagnosis and treatment," Merck argued.

Similarly, GSK stated, "Therapies to reduce the risk of developing prostate cancer would be an important addition to current management options for both patients and prescribers." Based on results from REDUCE, 19 men at heightened risk of prostate cancer would need to take Avodart for 4 years to prevent one prostate cancer diagnosis, GSK added.

Internal Medicine News Digital Network and "The Pink Sheet" are published by Elsevier.

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

A Food and Drug Administration advisory committee is scheduled to discuss the criteria for a claim of preventing NSAID-triggered gastrointestinal complications at a Nov. 4 meeting.

The agency is continuing to refine its criteria for approving label claims that tout improved GI safety for NSAIDs.

At the meeting, the agency will ask its Gastrointestinal Drugs Advisory Committee to discuss whether endoscopically documented gastric ulcers are an adequate outcome measure to evaluate drugs that are intended to prevent such NSAID-triggered GI complications.

A recent trend in drug development is to combine NSAIDs with such drugs. For example, AstraZeneca’s Vimovo (naproxen/esomeprazole) was approved in April, with an indication of “relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis and to decrease the risk of developing gastric ulcers in patients at risk of developing NSAID associated gastric ulcers.”

But the agency is scrutinizing such combination claims closely. In late 2008, while Vimovo, which was codeveloped with Pozen Inc., was still in phase III clinical trials, the FDA began reassessing end point requirements for NSAID/proton pump inhibitor products to address inconsistencies between the Gastroenterology Drugs Division and the Analgesics, Anesthetics, and Rheumatology Products Division.

This created a worrisome situation for Pozen, which had a special protocol assessment in place, a written agreement under which the FDA had agreed to allow the company to use gastric ulcer reduction as measured by endoscopy as a primary end point. The company hinted at the time that it would consider suing the agency to enforce the special protocol assessment.

Other products may still be on the hot seat. Currently under review is Horizon Pharma Inc.’s New Drug Application for Duexa (ibuprofen/famotidine), a fixed-dose tablet formulation of the NSAID and a high dose of the H2 antagonist to reduce the risk of development of upper gastrointestinal ulcers in patients with arthritis and pain.

In what may well be an ominous sign of things to come, the FDA’s “complete response” letter to NicOx Inc. for its naproxcinod called for the firm to do additional safety studies and demonstrate the clinical benefit it was claiming of prevention of gastropathy and elevated blood pressure triggered by the NSAID. This followed a negative vote by the FDA’s Drug Safety and Risk Management Committee and Arthritis Advisory Committee on May 12.

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

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. The Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions in middle September that data from the trial were sufficient to demonstrate efficacy, 10-1 with 2 abstentions that the data could be applied to the U.S. population, 12-0 with 1 abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug's current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that's comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo. “It's rare to see data this robust to show the efficacy, although it's from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA's official view going into the meeting was almost unequivocally positive as well. “I think we've made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions.…I think we feel that we've adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA's division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

The data are “reliable in support of the application,” she said.

This newspaper and “The Pink Sheet” are published by Elsevier.

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. The Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions in middle September that data from the trial were sufficient to demonstrate efficacy, 10-1 with 2 abstentions that the data could be applied to the U.S. population, 12-0 with 1 abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug's current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that's comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo. “It's rare to see data this robust to show the efficacy, although it's from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA's official view going into the meeting was almost unequivocally positive as well. “I think we've made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions.…I think we feel that we've adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA's division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

The data are “reliable in support of the application,” she said.

This newspaper and “The Pink Sheet” are published by Elsevier.

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. The Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions in middle September that data from the trial were sufficient to demonstrate efficacy, 10-1 with 2 abstentions that the data could be applied to the U.S. population, 12-0 with 1 abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug's current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient's health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that's comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo. “It's rare to see data this robust to show the efficacy, although it's from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA's official view going into the meeting was almost unequivocally positive as well. “I think we've made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions.…I think we feel that we've adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA's division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

The data are “reliable in support of the application,” she said.

This newspaper and “The Pink Sheet” are published by Elsevier.

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”

Naltrexone is safe and effective for the treatment of opioid abuse, but the company should build on existing labeling that calls for monitoring and support as essential parts of therapy, a Food and Drug Administration advisory panel said.

Lingering concerns about the applicability of the results from the single clinical trial, which was conducted in Russia, to the U.S. population were not enough to stem the tide of support. On Sept. 16, the Psychopharmacologic Drugs Advisory Committee voted 11-2 with no abstentions that data from the trial were sufficient to demonstrate efficacy, 10-1 with two abstentions that the data could be applied to the U.S. population, 12-0 with one abstention that the safety data were adequate, and 12-1 that the supplemental indication should be approved.

Alkermes Inc., maker of naltrexone under the name Vivitrol, has a head start on the monitoring and support question from the drug’s current label for alcohol abuse treatment, which states: “Alcohol-dependent patients, including those taking Vivitrol, should be monitored for the development of depression or suicidal thinking. Families and caregivers of patients being treated with Vivitrol should be alerted to the need to monitor patients for the emergence of symptoms of depression or suicidality, and to report such symptoms to the patient’s health care provider.”

The label also says that “patients should be advised that Vivitrol has been shown to treat alcohol dependence only when used as part of a treatment program that includes counseling and support.”

Citing a presentation delivered on behalf of Alkermes by Dr. Paul Earley, medical director of the Talbott Recovery Campus, panel member Chung-yui Betty Tai, Ph.D., of the National Institute on Drug Abuse, said that Vivitrol “is a good medication for young [patients with a] short addiction history [who are] highly motivated, such as addicted professionals, and also with strong social and family support. Based on those, I think that’s comparable to the Russian population in the study, based on the report I have reviewed.”

“I am of the belief that no one piece of treatment decides totally what the outcome is,” Louis Baxter, executive medical director of the Professional Assistance Program of New Jersey, said. “So using this medicine in conjunction with the other elements of addiction treatment, I believe that we will actually be able to observe those same results [as in the Russian trial] and perhaps even better.”

‘It’s Rare to See Data This Robust’

Data from an intent-to-treat analysis of the 250 patients enrolled in the study showed that the 126 patients treated once monthly with Vivitrol had 90% opioid-free urine screens, compared with 35% for the 124 patients taking a placebo.

“It’s rare to see data this robust to show the efficacy, although it’s from a single trial,” Dr. Tai said, citing her long experience doing clinical trials for drug addiction treatments.

The FDA’s official view going into the meeting was almost unequivocally positive as well. “I think we’ve made it clear that we agreed with the sponsor that they have demonstrated efficacy and that there are no particularly concerning new safety signals with this formulation. And really, we did not find any concerns related to the data integrity from the one study,” Dr. Bob Rappoport, director of the division of anesthesia and analgesia products, said. However, he added, “the single study done in Russia still raises questions. ... I think we feel that we’ve adequately addressed those questions to our level of comfort, but we want to hear from [the advisory committee].”

This apparently refers to a concern raised in background materials released before the meeting that there was a lower rate of adverse events in the Russian study than in prior studies conducted in the United States, and there might be a “cultural norm” in Russia of underreporting adverse events.

However, this question was addressed in a presentation by Dr. Tejashri Purohit-Sheth, branch chief for Good Clinical Practice 2 at the FDA’s division of scientific investigations, who said that the agency found in its inspection of 4 of the 13 Russian sites that “adverse event and serious adverse event reporting [were] adequate,” and that there was “no evidence of underreporting.”

“The data is reliable in support of the application,” she said.

That didn’t mean the committee found Vivitrol to be completely free of all safety concerns, such as the risk that addicts taking the drug and finding their cravings suppressed will take more opioid to try to get high and end up overdosing. But the general sense of the committee seemed to be expressed by Dr. Michael Hwang of Robert Wood Johnson Medical School, who said, “All medications inherently carry some risks, and given the scope of the [addiction] problem here, I think it is safe.”