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FDA provides flexibility to improve COVID-19 test availability
First, the FDA is giving states more flexibility to approve and implement testing for COVID-19.
“States can set up a system in which they take responsibility for authorizing such tests and the laboratories will not engage with the FDA,” agency Commissioner Stephen Hahn, MD, said in a March 16 statement announcing the policy updates. “Laboratories developing tests in these states can engage directly with the appropriate state authorities, instead of with the FDA.”
A copy of the updated guidance document can be found here.
Dr. Hahn added that laboratories working within this authority granted to states will not have to pursue an emergency use authorization (EUA). New York state was previously granted a waiver to allow for more state oversight over the introduction of diagnostic testing.
Second, the FDA is expanding guidance issued on Feb. 29 on who can develop diagnostic tests. Originally, the Feb. 29 guidance was aimed at labs certified to perform high-complexity testing consistent with requirements outlined in the Clinical Laboratory Improvement Amendments.
“Under the update published today, the agency does not intend to object to commercial manufacturers distributing and labs using new commercially developed tests prior to the FDA granting an EUA, under certain circumstances,” Commissioner Hahn said, adding that a number of commercial manufacturers are developing tests for the coronavirus with the intent of submitting an EUA request.
“During this public health emergency, the FDA does not intend to object to the distribution and use of these tests for specimen testing for a reasonable period of time after the manufacturer’s validation of the test while the manufacturer is preparing its EUA request,” he added.
The updated guidance also provides recommendations for test developers working on serologic tests for COVID-19.
During a March 16 conference call with reporters, Commissioner Hahn said the flexibility would add a “significant number of tests and we believe this will be a surge to meet the demand that we expect to see, although it is somewhat difficult” to quantify the number of tests this new flexibility will bring to the market.
First, the FDA is giving states more flexibility to approve and implement testing for COVID-19.
“States can set up a system in which they take responsibility for authorizing such tests and the laboratories will not engage with the FDA,” agency Commissioner Stephen Hahn, MD, said in a March 16 statement announcing the policy updates. “Laboratories developing tests in these states can engage directly with the appropriate state authorities, instead of with the FDA.”
A copy of the updated guidance document can be found here.
Dr. Hahn added that laboratories working within this authority granted to states will not have to pursue an emergency use authorization (EUA). New York state was previously granted a waiver to allow for more state oversight over the introduction of diagnostic testing.
Second, the FDA is expanding guidance issued on Feb. 29 on who can develop diagnostic tests. Originally, the Feb. 29 guidance was aimed at labs certified to perform high-complexity testing consistent with requirements outlined in the Clinical Laboratory Improvement Amendments.
“Under the update published today, the agency does not intend to object to commercial manufacturers distributing and labs using new commercially developed tests prior to the FDA granting an EUA, under certain circumstances,” Commissioner Hahn said, adding that a number of commercial manufacturers are developing tests for the coronavirus with the intent of submitting an EUA request.
“During this public health emergency, the FDA does not intend to object to the distribution and use of these tests for specimen testing for a reasonable period of time after the manufacturer’s validation of the test while the manufacturer is preparing its EUA request,” he added.
The updated guidance also provides recommendations for test developers working on serologic tests for COVID-19.
During a March 16 conference call with reporters, Commissioner Hahn said the flexibility would add a “significant number of tests and we believe this will be a surge to meet the demand that we expect to see, although it is somewhat difficult” to quantify the number of tests this new flexibility will bring to the market.
First, the FDA is giving states more flexibility to approve and implement testing for COVID-19.
“States can set up a system in which they take responsibility for authorizing such tests and the laboratories will not engage with the FDA,” agency Commissioner Stephen Hahn, MD, said in a March 16 statement announcing the policy updates. “Laboratories developing tests in these states can engage directly with the appropriate state authorities, instead of with the FDA.”
A copy of the updated guidance document can be found here.
Dr. Hahn added that laboratories working within this authority granted to states will not have to pursue an emergency use authorization (EUA). New York state was previously granted a waiver to allow for more state oversight over the introduction of diagnostic testing.
Second, the FDA is expanding guidance issued on Feb. 29 on who can develop diagnostic tests. Originally, the Feb. 29 guidance was aimed at labs certified to perform high-complexity testing consistent with requirements outlined in the Clinical Laboratory Improvement Amendments.
“Under the update published today, the agency does not intend to object to commercial manufacturers distributing and labs using new commercially developed tests prior to the FDA granting an EUA, under certain circumstances,” Commissioner Hahn said, adding that a number of commercial manufacturers are developing tests for the coronavirus with the intent of submitting an EUA request.
“During this public health emergency, the FDA does not intend to object to the distribution and use of these tests for specimen testing for a reasonable period of time after the manufacturer’s validation of the test while the manufacturer is preparing its EUA request,” he added.
The updated guidance also provides recommendations for test developers working on serologic tests for COVID-19.
During a March 16 conference call with reporters, Commissioner Hahn said the flexibility would add a “significant number of tests and we believe this will be a surge to meet the demand that we expect to see, although it is somewhat difficult” to quantify the number of tests this new flexibility will bring to the market.
Trump to governors: Don’t wait for feds on medical supplies
President Donald Trump has advised state governors not to wait on the federal government when it comes to ensuring readiness for a surge in patients from the COVID-19 outbreak.
“If they are able to get ventilators, respirators, if they are able to get certain things without having to go through the longer process of federal government,” they should order on their own and bypass the federal government ordering system, the president stated during a March 16 press briefing.
That being said, he noted that the federal government is “ordering tremendous numbers of ventilators, respirators, [and] masks,” although he could not give a specific number on how much has been ordered or how many has already been stockpiled.
“It is always going to be faster if they can get them directly, if they need them, and I have given them authorization to order directly,” President Trump said.
The comments came as the White House revised recommendations on gatherings. The new guidelines now limit gatherings to no more than 10 people. Officials are further advising Americans to self-quarantine for 2 weeks if they are sick, if someone in their house is sick, or if someone in their house has tested positive for COVID-19.
Additionally, the White House called on Americans to limit discretionary travel and to avoid eating and drinking in restaurants, bars, and food courts during the next 15 days, even if they are feeling healthy and are asymptomatic.
“With several weeks of focused action, we can turn the corner and turn it quickly,” the president said.
In terms of testing, the Food and Drug Administration has granted emergency use authorization to two commercial diagnostic tests: Thermo Fisher for its TaqPath COVID-19 Combo Kit and Roche for its cobas SARS-CoV-2 test. White House officials said up to 1 million tests will be available this week, with 2 million next week.
The president also announced that phase 1 testing of a vaccine has begun. The test involves more than 40 healthy volunteers in the Seattle area who will receive three shots over the trial period. Phase 1 testing is generally conducted to determine safety of a new therapeutic.
President Donald Trump has advised state governors not to wait on the federal government when it comes to ensuring readiness for a surge in patients from the COVID-19 outbreak.
“If they are able to get ventilators, respirators, if they are able to get certain things without having to go through the longer process of federal government,” they should order on their own and bypass the federal government ordering system, the president stated during a March 16 press briefing.
That being said, he noted that the federal government is “ordering tremendous numbers of ventilators, respirators, [and] masks,” although he could not give a specific number on how much has been ordered or how many has already been stockpiled.
“It is always going to be faster if they can get them directly, if they need them, and I have given them authorization to order directly,” President Trump said.
The comments came as the White House revised recommendations on gatherings. The new guidelines now limit gatherings to no more than 10 people. Officials are further advising Americans to self-quarantine for 2 weeks if they are sick, if someone in their house is sick, or if someone in their house has tested positive for COVID-19.
Additionally, the White House called on Americans to limit discretionary travel and to avoid eating and drinking in restaurants, bars, and food courts during the next 15 days, even if they are feeling healthy and are asymptomatic.
“With several weeks of focused action, we can turn the corner and turn it quickly,” the president said.
In terms of testing, the Food and Drug Administration has granted emergency use authorization to two commercial diagnostic tests: Thermo Fisher for its TaqPath COVID-19 Combo Kit and Roche for its cobas SARS-CoV-2 test. White House officials said up to 1 million tests will be available this week, with 2 million next week.
The president also announced that phase 1 testing of a vaccine has begun. The test involves more than 40 healthy volunteers in the Seattle area who will receive three shots over the trial period. Phase 1 testing is generally conducted to determine safety of a new therapeutic.
President Donald Trump has advised state governors not to wait on the federal government when it comes to ensuring readiness for a surge in patients from the COVID-19 outbreak.
“If they are able to get ventilators, respirators, if they are able to get certain things without having to go through the longer process of federal government,” they should order on their own and bypass the federal government ordering system, the president stated during a March 16 press briefing.
That being said, he noted that the federal government is “ordering tremendous numbers of ventilators, respirators, [and] masks,” although he could not give a specific number on how much has been ordered or how many has already been stockpiled.
“It is always going to be faster if they can get them directly, if they need them, and I have given them authorization to order directly,” President Trump said.
The comments came as the White House revised recommendations on gatherings. The new guidelines now limit gatherings to no more than 10 people. Officials are further advising Americans to self-quarantine for 2 weeks if they are sick, if someone in their house is sick, or if someone in their house has tested positive for COVID-19.
Additionally, the White House called on Americans to limit discretionary travel and to avoid eating and drinking in restaurants, bars, and food courts during the next 15 days, even if they are feeling healthy and are asymptomatic.
“With several weeks of focused action, we can turn the corner and turn it quickly,” the president said.
In terms of testing, the Food and Drug Administration has granted emergency use authorization to two commercial diagnostic tests: Thermo Fisher for its TaqPath COVID-19 Combo Kit and Roche for its cobas SARS-CoV-2 test. White House officials said up to 1 million tests will be available this week, with 2 million next week.
The president also announced that phase 1 testing of a vaccine has begun. The test involves more than 40 healthy volunteers in the Seattle area who will receive three shots over the trial period. Phase 1 testing is generally conducted to determine safety of a new therapeutic.
FDA warns of serious infection risk after FMT
The Food and Drug Administration has issued a Safety Alert warning of the potential risk of serious, life-threatening infection in patients who receive fecal microbiota transplant for Clostridioides difficile infection.
The FDA has received six reports of infection associated with fecal microbiota transplant from a stool bank company based in the United States: Two patients had enteropathogenic Escherichia coli (EPEC) infection, and four had shiga toxin–producing E. coli (STEC). The two EPEC infections came from two separate donors, but the four STEC infections came from a single donor, according to the FDA.
In addition, two patients died after receiving fecal microbiota transplant from the donor associated with the STEC infections. These patients died before any of the STEC infections were reported to the FDA; as their stool was not tested for STEC, it is unclear whether it contributed to their deaths.
The use of fecal microbiota transplant is still investigational, and as such, patients should be made aware by health care providers of the risks, which include the potential for transmission of pathogenic bacteria and the resultant adverse events, the FDA said in the press release.
The Food and Drug Administration has issued a Safety Alert warning of the potential risk of serious, life-threatening infection in patients who receive fecal microbiota transplant for Clostridioides difficile infection.
The FDA has received six reports of infection associated with fecal microbiota transplant from a stool bank company based in the United States: Two patients had enteropathogenic Escherichia coli (EPEC) infection, and four had shiga toxin–producing E. coli (STEC). The two EPEC infections came from two separate donors, but the four STEC infections came from a single donor, according to the FDA.
In addition, two patients died after receiving fecal microbiota transplant from the donor associated with the STEC infections. These patients died before any of the STEC infections were reported to the FDA; as their stool was not tested for STEC, it is unclear whether it contributed to their deaths.
The use of fecal microbiota transplant is still investigational, and as such, patients should be made aware by health care providers of the risks, which include the potential for transmission of pathogenic bacteria and the resultant adverse events, the FDA said in the press release.
The Food and Drug Administration has issued a Safety Alert warning of the potential risk of serious, life-threatening infection in patients who receive fecal microbiota transplant for Clostridioides difficile infection.
The FDA has received six reports of infection associated with fecal microbiota transplant from a stool bank company based in the United States: Two patients had enteropathogenic Escherichia coli (EPEC) infection, and four had shiga toxin–producing E. coli (STEC). The two EPEC infections came from two separate donors, but the four STEC infections came from a single donor, according to the FDA.
In addition, two patients died after receiving fecal microbiota transplant from the donor associated with the STEC infections. These patients died before any of the STEC infections were reported to the FDA; as their stool was not tested for STEC, it is unclear whether it contributed to their deaths.
The use of fecal microbiota transplant is still investigational, and as such, patients should be made aware by health care providers of the risks, which include the potential for transmission of pathogenic bacteria and the resultant adverse events, the FDA said in the press release.
FDA to revise safety evaluation of type 2 diabetes drugs
The US Food and Drug Administration (FDA) has issued new draft guidance for industry on evaluating the safety of new drugs for type 2 diabetes and removed the “outdated” 12-year-old requirement for standardized cardiovascular outcomes trials (CVOTs).
The new draft guidance, “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control,” will replace the December 2008 requirement that manufacturers conduct CVOTs to rule out unacceptable cardiovascular safety risk. That move followed concerns raised at the time about the thiazolidinedione class of glucose-lowering drugs.
Since then, “FDA has reviewed the results of several [CVOTs] conducted to meet the December 2008 guidance recommendations. None of the CVOTs to date have identified an increased risk of ischemic cardiovascular events; some of the CVOTs have instead demonstrated a reduced risk for cardiovascular events,” according to the federal register announcement.
In October 2018, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee narrowly voted (10 to 9) to continue requiring CVOTs, but most panel members also recommended some changes to them, including requirements for safety data beyond cardiovascular events.
Based on the CVOT results over the years and the panel’s recommendations, “FDA is revisiting the recommendations of the December 2008 guidance and is now proposing an updated approach to evaluating the safety of new drugs and biologics to improve glycemic control.”
“The new draft guidance does not contain the recommendation that sponsors of all new therapies for type 2 diabetes uniformly rule out a specific degree of risk for ischemic cardiovascular adverse outcomes,” the FDA said.
Instead, the draft calls for at least 4000 patient-years of exposure to the new drug in phase 3 trials and inclusion of study participants with comorbid conditions and/or diabetes complications, including at least 500 with stage 3-4 chronic kidney disease, 600 with established cardiovascular disease, and at least 600 over the age of 65 years.
The FDA is soliciting stakeholder input on these and other issues, including study duration, subject demographics, specific safety concerns, and event adjudication.
In a statement, Lisa Yanoff, MD, acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said: “By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications.”
The draft is open for comments for 90 days after March 9, 2020. It is available online, along with a link for submitting comments.
This article first appeared on Medscape.com.
The US Food and Drug Administration (FDA) has issued new draft guidance for industry on evaluating the safety of new drugs for type 2 diabetes and removed the “outdated” 12-year-old requirement for standardized cardiovascular outcomes trials (CVOTs).
The new draft guidance, “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control,” will replace the December 2008 requirement that manufacturers conduct CVOTs to rule out unacceptable cardiovascular safety risk. That move followed concerns raised at the time about the thiazolidinedione class of glucose-lowering drugs.
Since then, “FDA has reviewed the results of several [CVOTs] conducted to meet the December 2008 guidance recommendations. None of the CVOTs to date have identified an increased risk of ischemic cardiovascular events; some of the CVOTs have instead demonstrated a reduced risk for cardiovascular events,” according to the federal register announcement.
In October 2018, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee narrowly voted (10 to 9) to continue requiring CVOTs, but most panel members also recommended some changes to them, including requirements for safety data beyond cardiovascular events.
Based on the CVOT results over the years and the panel’s recommendations, “FDA is revisiting the recommendations of the December 2008 guidance and is now proposing an updated approach to evaluating the safety of new drugs and biologics to improve glycemic control.”
“The new draft guidance does not contain the recommendation that sponsors of all new therapies for type 2 diabetes uniformly rule out a specific degree of risk for ischemic cardiovascular adverse outcomes,” the FDA said.
Instead, the draft calls for at least 4000 patient-years of exposure to the new drug in phase 3 trials and inclusion of study participants with comorbid conditions and/or diabetes complications, including at least 500 with stage 3-4 chronic kidney disease, 600 with established cardiovascular disease, and at least 600 over the age of 65 years.
The FDA is soliciting stakeholder input on these and other issues, including study duration, subject demographics, specific safety concerns, and event adjudication.
In a statement, Lisa Yanoff, MD, acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said: “By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications.”
The draft is open for comments for 90 days after March 9, 2020. It is available online, along with a link for submitting comments.
This article first appeared on Medscape.com.
The US Food and Drug Administration (FDA) has issued new draft guidance for industry on evaluating the safety of new drugs for type 2 diabetes and removed the “outdated” 12-year-old requirement for standardized cardiovascular outcomes trials (CVOTs).
The new draft guidance, “Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control,” will replace the December 2008 requirement that manufacturers conduct CVOTs to rule out unacceptable cardiovascular safety risk. That move followed concerns raised at the time about the thiazolidinedione class of glucose-lowering drugs.
Since then, “FDA has reviewed the results of several [CVOTs] conducted to meet the December 2008 guidance recommendations. None of the CVOTs to date have identified an increased risk of ischemic cardiovascular events; some of the CVOTs have instead demonstrated a reduced risk for cardiovascular events,” according to the federal register announcement.
In October 2018, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee narrowly voted (10 to 9) to continue requiring CVOTs, but most panel members also recommended some changes to them, including requirements for safety data beyond cardiovascular events.
Based on the CVOT results over the years and the panel’s recommendations, “FDA is revisiting the recommendations of the December 2008 guidance and is now proposing an updated approach to evaluating the safety of new drugs and biologics to improve glycemic control.”
“The new draft guidance does not contain the recommendation that sponsors of all new therapies for type 2 diabetes uniformly rule out a specific degree of risk for ischemic cardiovascular adverse outcomes,” the FDA said.
Instead, the draft calls for at least 4000 patient-years of exposure to the new drug in phase 3 trials and inclusion of study participants with comorbid conditions and/or diabetes complications, including at least 500 with stage 3-4 chronic kidney disease, 600 with established cardiovascular disease, and at least 600 over the age of 65 years.
The FDA is soliciting stakeholder input on these and other issues, including study duration, subject demographics, specific safety concerns, and event adjudication.
In a statement, Lisa Yanoff, MD, acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said: “By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications.”
The draft is open for comments for 90 days after March 9, 2020. It is available online, along with a link for submitting comments.
This article first appeared on Medscape.com.
FDA approves immunotherapy combo for liver cancer
Patients with advanced liver cancer have a new treatment option – the immunotherapy combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb).
The US Food and Drug Administration (FDA) granted an accelerated approval of the combination for use in patients with advanced hepatocellular carcinoma (HCC) who have previously been treated with sorafenib (Nexavar, Bayer). Nivolumab is already approved as monotherapy for use in advanced HCC in patients who have previously been treated with sorafenib.
The immunotherapy combination has shown a response rate that is more than twice that seen with nivolumab alone. The combination was tested at three different dosage schedules in the single-arm phase 1/2 trial known as CheckMate-040, which was conducted in 148 patients with advanced HCC who had previously been treated with sorafenib.
The approval was based on one arm of this trial, a cohort of 49 patients who were treated with nivolumab 1 mg/kg IV and ipilimumab 3 mg/kg IV every 3 weeks for four doses, followed by nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
After a minimum follow-up of 28 months, 33% (16/49) of these patients showed a response, with 8% (4/49) showing a complete response and 24% (12/49) a partial response.
In terms of duration of responses, 88% of the responses lasted at least 6 months, 56% at least 12 months, and 31% at least 24 months, according to the company.
The results that led to the 2017 approval of nivolumab monotherapy for advanced HCC, as previously reported by Medscape Medical News, come from a cohort of 154 patients who received nivolumab 3 mg/kg administered intravenously every 2 weeks.
The overall response rate was 14.3% (22 of 154 patients), with three patients (1.9%) showing a complete response and 19 patients (12.3%) a partial response. The duration of the responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of 6 months or longer, and 55% had responses of 12 months or longer.
Notably, patient responses in all arms were achieved regardless of baseline tumor PD-L1 status.
Aggressive disease, incidence is rising
“HCC is an aggressive disease in need of different treatment approaches,” said Anthony B. El-Khoueiry, MD, of the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, in a company press statement.“The overall response rate observed in the Opdivo + Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients,” he commented. El-Khoueiry was lead investigator of the study and has received honoraria and consulting fees from Bristol-Myers Squibb.
“The incidence of liver cancer is rising in the United States, and HCC is the most common and aggressive form of the disease,” said Andrea Wilson, president and founder, Blue Faery: The Adrienne Wilson Liver Cancer Association.
“Today’s approval provides a new option for patients with HCC previously treated with sorafenib, giving the community more hope,” she said in the company press statement.
Safety profile
The nivolumab-ipilimumab combination had an “acceptable” safety profile overall in the CheckMate-040 trial, wrote lead study author Thomas Yao, MD, of the University at Hong Kong, China, and colleagues in their study abstract, which was presented at the 2019 annual meeting of the American Society of Clinical Oncology. Yao has received honoraria from Bristol-Myers Squibb and has served as a consultant to the company.
According to those data, 37% of patients had a grade 3-4 treatment-related adverse event (TRAE), the most common of which were pruritus and rash; 5% had grade 3–4 TRAEs that led to discontinuation.
Nivolumab is associated with pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions, and infusion-related reactions, as well as embryo-fetal toxicity. Ipilimumab has a boxed warning for immune-mediated adverse reactions.
Nivolumab alone is approved for use in the treatment of unresectable or metastatic melanoma, non–small cell lung cancer, small cell lung cancer, and classical Hodgkin lymphoma.
The combination of nivolumab with ipilimumab is also approved for use in the treatment of melanoma and renal cell carcinoma.
This article first appeared on Medscape.com.
Patients with advanced liver cancer have a new treatment option – the immunotherapy combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb).
The US Food and Drug Administration (FDA) granted an accelerated approval of the combination for use in patients with advanced hepatocellular carcinoma (HCC) who have previously been treated with sorafenib (Nexavar, Bayer). Nivolumab is already approved as monotherapy for use in advanced HCC in patients who have previously been treated with sorafenib.
The immunotherapy combination has shown a response rate that is more than twice that seen with nivolumab alone. The combination was tested at three different dosage schedules in the single-arm phase 1/2 trial known as CheckMate-040, which was conducted in 148 patients with advanced HCC who had previously been treated with sorafenib.
The approval was based on one arm of this trial, a cohort of 49 patients who were treated with nivolumab 1 mg/kg IV and ipilimumab 3 mg/kg IV every 3 weeks for four doses, followed by nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
After a minimum follow-up of 28 months, 33% (16/49) of these patients showed a response, with 8% (4/49) showing a complete response and 24% (12/49) a partial response.
In terms of duration of responses, 88% of the responses lasted at least 6 months, 56% at least 12 months, and 31% at least 24 months, according to the company.
The results that led to the 2017 approval of nivolumab monotherapy for advanced HCC, as previously reported by Medscape Medical News, come from a cohort of 154 patients who received nivolumab 3 mg/kg administered intravenously every 2 weeks.
The overall response rate was 14.3% (22 of 154 patients), with three patients (1.9%) showing a complete response and 19 patients (12.3%) a partial response. The duration of the responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of 6 months or longer, and 55% had responses of 12 months or longer.
Notably, patient responses in all arms were achieved regardless of baseline tumor PD-L1 status.
Aggressive disease, incidence is rising
“HCC is an aggressive disease in need of different treatment approaches,” said Anthony B. El-Khoueiry, MD, of the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, in a company press statement.“The overall response rate observed in the Opdivo + Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients,” he commented. El-Khoueiry was lead investigator of the study and has received honoraria and consulting fees from Bristol-Myers Squibb.
“The incidence of liver cancer is rising in the United States, and HCC is the most common and aggressive form of the disease,” said Andrea Wilson, president and founder, Blue Faery: The Adrienne Wilson Liver Cancer Association.
“Today’s approval provides a new option for patients with HCC previously treated with sorafenib, giving the community more hope,” she said in the company press statement.
Safety profile
The nivolumab-ipilimumab combination had an “acceptable” safety profile overall in the CheckMate-040 trial, wrote lead study author Thomas Yao, MD, of the University at Hong Kong, China, and colleagues in their study abstract, which was presented at the 2019 annual meeting of the American Society of Clinical Oncology. Yao has received honoraria from Bristol-Myers Squibb and has served as a consultant to the company.
According to those data, 37% of patients had a grade 3-4 treatment-related adverse event (TRAE), the most common of which were pruritus and rash; 5% had grade 3–4 TRAEs that led to discontinuation.
Nivolumab is associated with pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions, and infusion-related reactions, as well as embryo-fetal toxicity. Ipilimumab has a boxed warning for immune-mediated adverse reactions.
Nivolumab alone is approved for use in the treatment of unresectable or metastatic melanoma, non–small cell lung cancer, small cell lung cancer, and classical Hodgkin lymphoma.
The combination of nivolumab with ipilimumab is also approved for use in the treatment of melanoma and renal cell carcinoma.
This article first appeared on Medscape.com.
Patients with advanced liver cancer have a new treatment option – the immunotherapy combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb).
The US Food and Drug Administration (FDA) granted an accelerated approval of the combination for use in patients with advanced hepatocellular carcinoma (HCC) who have previously been treated with sorafenib (Nexavar, Bayer). Nivolumab is already approved as monotherapy for use in advanced HCC in patients who have previously been treated with sorafenib.
The immunotherapy combination has shown a response rate that is more than twice that seen with nivolumab alone. The combination was tested at three different dosage schedules in the single-arm phase 1/2 trial known as CheckMate-040, which was conducted in 148 patients with advanced HCC who had previously been treated with sorafenib.
The approval was based on one arm of this trial, a cohort of 49 patients who were treated with nivolumab 1 mg/kg IV and ipilimumab 3 mg/kg IV every 3 weeks for four doses, followed by nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity.
After a minimum follow-up of 28 months, 33% (16/49) of these patients showed a response, with 8% (4/49) showing a complete response and 24% (12/49) a partial response.
In terms of duration of responses, 88% of the responses lasted at least 6 months, 56% at least 12 months, and 31% at least 24 months, according to the company.
The results that led to the 2017 approval of nivolumab monotherapy for advanced HCC, as previously reported by Medscape Medical News, come from a cohort of 154 patients who received nivolumab 3 mg/kg administered intravenously every 2 weeks.
The overall response rate was 14.3% (22 of 154 patients), with three patients (1.9%) showing a complete response and 19 patients (12.3%) a partial response. The duration of the responses ranged from 3.2 to 38.2+ months; 91% of those patients had responses of 6 months or longer, and 55% had responses of 12 months or longer.
Notably, patient responses in all arms were achieved regardless of baseline tumor PD-L1 status.
Aggressive disease, incidence is rising
“HCC is an aggressive disease in need of different treatment approaches,” said Anthony B. El-Khoueiry, MD, of the Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, in a company press statement.“The overall response rate observed in the Opdivo + Yervoy cohort of the CheckMate-040 trial underscores the potential of this dual immunotherapy as a possible treatment option for patients,” he commented. El-Khoueiry was lead investigator of the study and has received honoraria and consulting fees from Bristol-Myers Squibb.
“The incidence of liver cancer is rising in the United States, and HCC is the most common and aggressive form of the disease,” said Andrea Wilson, president and founder, Blue Faery: The Adrienne Wilson Liver Cancer Association.
“Today’s approval provides a new option for patients with HCC previously treated with sorafenib, giving the community more hope,” she said in the company press statement.
Safety profile
The nivolumab-ipilimumab combination had an “acceptable” safety profile overall in the CheckMate-040 trial, wrote lead study author Thomas Yao, MD, of the University at Hong Kong, China, and colleagues in their study abstract, which was presented at the 2019 annual meeting of the American Society of Clinical Oncology. Yao has received honoraria from Bristol-Myers Squibb and has served as a consultant to the company.
According to those data, 37% of patients had a grade 3-4 treatment-related adverse event (TRAE), the most common of which were pruritus and rash; 5% had grade 3–4 TRAEs that led to discontinuation.
Nivolumab is associated with pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions, and infusion-related reactions, as well as embryo-fetal toxicity. Ipilimumab has a boxed warning for immune-mediated adverse reactions.
Nivolumab alone is approved for use in the treatment of unresectable or metastatic melanoma, non–small cell lung cancer, small cell lung cancer, and classical Hodgkin lymphoma.
The combination of nivolumab with ipilimumab is also approved for use in the treatment of melanoma and renal cell carcinoma.
This article first appeared on Medscape.com.
FDA cancels or postpones meetings amid COVID-19 concerns
Officials at the Food and Drug Administration’s Center for Drug Evaluation and Research are taking the precautionary step of canceling or postponing advisory committee meetings and limiting staff travel in an effort to help curb the spread of the COVID-19.
“The outbreak of respiratory illness caused by a novel coronavirus, COVID-19, that started in China is spreading to other countries, including the United States,” CDER Director Janet Woodcock, MD, said in a memo to CDER staff. “As a precaution, FDA is canceling foreign official agency travel and limiting domestic travel to mission critical only, effective immediately and through April.”
Additionally, the memo notes that “CDER-organized external meetings, conferences, and workshops will be postponed or canceled from March 10 through April.”
“To mitigate the impact on our work, I encourage you to hold meetings with external stakeholders through teleconference, when possible,” she wrote.
Thus far, only a few CDER events on the FDA’s meeting webpage are listed as being canceled or postponed. Some of the affected meetings include a March 10 public meeting on patient-focused drug development for stimulant-use disorder, a March 11 meeting of the Nonprescription Drug Advisory Committee, and a March 30 public meeting on patient-focused drug development for vitiligo, all of which are postponed until further notice. The Center for Biologics Evaluation and Research also has postponed until further notice its U.S.–Japan Cellular and Gene Therapy Conference, originally scheduled for March 12.
Dr. Woodcock also noted in the memo that in relation to inspections, “we plan to use technology and established agreements with our foreign counterparts to minimize disruptions to the drug supply chain and to applications under review, so that Americans can continue to get their medications.”
Officials at the Food and Drug Administration’s Center for Drug Evaluation and Research are taking the precautionary step of canceling or postponing advisory committee meetings and limiting staff travel in an effort to help curb the spread of the COVID-19.
“The outbreak of respiratory illness caused by a novel coronavirus, COVID-19, that started in China is spreading to other countries, including the United States,” CDER Director Janet Woodcock, MD, said in a memo to CDER staff. “As a precaution, FDA is canceling foreign official agency travel and limiting domestic travel to mission critical only, effective immediately and through April.”
Additionally, the memo notes that “CDER-organized external meetings, conferences, and workshops will be postponed or canceled from March 10 through April.”
“To mitigate the impact on our work, I encourage you to hold meetings with external stakeholders through teleconference, when possible,” she wrote.
Thus far, only a few CDER events on the FDA’s meeting webpage are listed as being canceled or postponed. Some of the affected meetings include a March 10 public meeting on patient-focused drug development for stimulant-use disorder, a March 11 meeting of the Nonprescription Drug Advisory Committee, and a March 30 public meeting on patient-focused drug development for vitiligo, all of which are postponed until further notice. The Center for Biologics Evaluation and Research also has postponed until further notice its U.S.–Japan Cellular and Gene Therapy Conference, originally scheduled for March 12.
Dr. Woodcock also noted in the memo that in relation to inspections, “we plan to use technology and established agreements with our foreign counterparts to minimize disruptions to the drug supply chain and to applications under review, so that Americans can continue to get their medications.”
Officials at the Food and Drug Administration’s Center for Drug Evaluation and Research are taking the precautionary step of canceling or postponing advisory committee meetings and limiting staff travel in an effort to help curb the spread of the COVID-19.
“The outbreak of respiratory illness caused by a novel coronavirus, COVID-19, that started in China is spreading to other countries, including the United States,” CDER Director Janet Woodcock, MD, said in a memo to CDER staff. “As a precaution, FDA is canceling foreign official agency travel and limiting domestic travel to mission critical only, effective immediately and through April.”
Additionally, the memo notes that “CDER-organized external meetings, conferences, and workshops will be postponed or canceled from March 10 through April.”
“To mitigate the impact on our work, I encourage you to hold meetings with external stakeholders through teleconference, when possible,” she wrote.
Thus far, only a few CDER events on the FDA’s meeting webpage are listed as being canceled or postponed. Some of the affected meetings include a March 10 public meeting on patient-focused drug development for stimulant-use disorder, a March 11 meeting of the Nonprescription Drug Advisory Committee, and a March 30 public meeting on patient-focused drug development for vitiligo, all of which are postponed until further notice. The Center for Biologics Evaluation and Research also has postponed until further notice its U.S.–Japan Cellular and Gene Therapy Conference, originally scheduled for March 12.
Dr. Woodcock also noted in the memo that in relation to inspections, “we plan to use technology and established agreements with our foreign counterparts to minimize disruptions to the drug supply chain and to applications under review, so that Americans can continue to get their medications.”
Osilodrostat gets FDA go-ahead for Cushing’s disease in adults
who either are not good candidates for pituitary gland surgery – the recommended first-line therapy – or in whom the disease persists after surgery.
Cushing’s disease is a rare condition caused when a pituitary tumor releases too much of the hormone adrenocorticotropin, which in turn, triggers the adrenal gland to overproduce cortisol. The condition is associated with serious health complications, including high blood pressure, obesity, type 2 diabetes, and compromised immunity.
Osilodrostat is the first therapy approved by the FDA to tackle the overproduction of cortisol, which it does by blocking the 11-beta-hydroxylase enzyme and thus preventing cortisol synthesis, the agency said in a press release.
In November 2019, the European Medicines Agency recommended the granting of a marketing authorization for osilodrostat, also for treating adults with Cushing’s disease.
The U.S. approval was based on outcomes from a study that evaluated the drug’s safety and efficacy in 137 adults with Cushing’s disease who had undergone pituitary surgery but were not cured, or who were not surgical candidates, according the release. About three-quarters of the patients were women, and the mean age was 41 years.
All of the patients started a 24-week, single-arm, open-label period at a dose of 2 mg of osilodrostat twice daily that could be increased every 2 weeks to 30 mg twice daily.
By week 24, cortisol levels in roughly half the patients were within the normal range, and 71 patients who did not need any more dose increases and who tolerated the drug were randomized to either osilodrostat or placebo for an 8-week withdrawal study. At the end of that time, 86% of the osilodrostat patients maintained their normal-range cortisol levels, compared with 30% of those taking placebo.
Osilodrostat is taken as an oral tablet twice a day, in the morning and evening. Among the common side effects reported in the study were adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema, although hypocortisolism, QTc prolongation, and elevations in adrenal hormone precursors, and androgens may also occur, according to the release.
The drug had been given an Orphan Drug Designation in recognition of its intended use in the treatment of a rare disease. The approval was granted to Novartis.
who either are not good candidates for pituitary gland surgery – the recommended first-line therapy – or in whom the disease persists after surgery.
Cushing’s disease is a rare condition caused when a pituitary tumor releases too much of the hormone adrenocorticotropin, which in turn, triggers the adrenal gland to overproduce cortisol. The condition is associated with serious health complications, including high blood pressure, obesity, type 2 diabetes, and compromised immunity.
Osilodrostat is the first therapy approved by the FDA to tackle the overproduction of cortisol, which it does by blocking the 11-beta-hydroxylase enzyme and thus preventing cortisol synthesis, the agency said in a press release.
In November 2019, the European Medicines Agency recommended the granting of a marketing authorization for osilodrostat, also for treating adults with Cushing’s disease.
The U.S. approval was based on outcomes from a study that evaluated the drug’s safety and efficacy in 137 adults with Cushing’s disease who had undergone pituitary surgery but were not cured, or who were not surgical candidates, according the release. About three-quarters of the patients were women, and the mean age was 41 years.
All of the patients started a 24-week, single-arm, open-label period at a dose of 2 mg of osilodrostat twice daily that could be increased every 2 weeks to 30 mg twice daily.
By week 24, cortisol levels in roughly half the patients were within the normal range, and 71 patients who did not need any more dose increases and who tolerated the drug were randomized to either osilodrostat or placebo for an 8-week withdrawal study. At the end of that time, 86% of the osilodrostat patients maintained their normal-range cortisol levels, compared with 30% of those taking placebo.
Osilodrostat is taken as an oral tablet twice a day, in the morning and evening. Among the common side effects reported in the study were adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema, although hypocortisolism, QTc prolongation, and elevations in adrenal hormone precursors, and androgens may also occur, according to the release.
The drug had been given an Orphan Drug Designation in recognition of its intended use in the treatment of a rare disease. The approval was granted to Novartis.
who either are not good candidates for pituitary gland surgery – the recommended first-line therapy – or in whom the disease persists after surgery.
Cushing’s disease is a rare condition caused when a pituitary tumor releases too much of the hormone adrenocorticotropin, which in turn, triggers the adrenal gland to overproduce cortisol. The condition is associated with serious health complications, including high blood pressure, obesity, type 2 diabetes, and compromised immunity.
Osilodrostat is the first therapy approved by the FDA to tackle the overproduction of cortisol, which it does by blocking the 11-beta-hydroxylase enzyme and thus preventing cortisol synthesis, the agency said in a press release.
In November 2019, the European Medicines Agency recommended the granting of a marketing authorization for osilodrostat, also for treating adults with Cushing’s disease.
The U.S. approval was based on outcomes from a study that evaluated the drug’s safety and efficacy in 137 adults with Cushing’s disease who had undergone pituitary surgery but were not cured, or who were not surgical candidates, according the release. About three-quarters of the patients were women, and the mean age was 41 years.
All of the patients started a 24-week, single-arm, open-label period at a dose of 2 mg of osilodrostat twice daily that could be increased every 2 weeks to 30 mg twice daily.
By week 24, cortisol levels in roughly half the patients were within the normal range, and 71 patients who did not need any more dose increases and who tolerated the drug were randomized to either osilodrostat or placebo for an 8-week withdrawal study. At the end of that time, 86% of the osilodrostat patients maintained their normal-range cortisol levels, compared with 30% of those taking placebo.
Osilodrostat is taken as an oral tablet twice a day, in the morning and evening. Among the common side effects reported in the study were adrenal insufficiency, headache, vomiting, nausea, fatigue, and edema, although hypocortisolism, QTc prolongation, and elevations in adrenal hormone precursors, and androgens may also occur, according to the release.
The drug had been given an Orphan Drug Designation in recognition of its intended use in the treatment of a rare disease. The approval was granted to Novartis.
Arsenic levels in infant rice cereal are down
according to test results released by the Food and Drug Administration.
In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.
Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.
The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.
“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.
“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.
according to test results released by the Food and Drug Administration.
In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.
Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.
The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.
“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.
“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.
according to test results released by the Food and Drug Administration.
In April 2016, the FDA issued draft guidance calling for manufacturers of the product to reduce the level of arsenic in their cereals by establishing an action level of arsenic of 100 mcg/kg or 100 parts per billion.
Seventy-six percent of samples of infant rice cereal tested in 2018 had levels of arsenic at or below 100 parts per billion versus 47% of samples tested in 2014, according to a statement from the FDA. In 2011-2013, an even lower percentage of samples tested contained amounts of inorganic arsenic at or below the FDA’s current action level for this element, whose consumption has been associated with cancer, skin lesions, cardiovascular diseases, and diabetes.
The 2018 data is based on the testing of 149 samples of infant white and brown rice cereal samples.
“Results from our tests show that manufacturers have made significant progress in ensuring lower levels of inorganic arsenic in infant rice cereal,” Susan Mayne, PhD, director of the Center for Food Safety and Applied Nutrition, said in the FDA statement.
“Both white rice and brown rice cereals showed improvement in meeting the FDA’s 100 ppb proposed action level, but the improvement was greatest for white rice cereals, which tend to have lower levels of inorganic arsenic overall,” according to the statement.
Testing lab asks FDA to recall NDMA-tainted metformin
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
Valisure, an online pharmacy and analytical laboratory based in New Haven, Conn., has asked the U.S. Food and Drug Administration to request recalls of the diabetes drug metformin from 11 companies after its own testing found levels of the probable carcinogen N-nitrosodimethylamine (NDMA) exceeded those recognized by the agency as being safe, according to a petition filed with the FDA.
“The presence of this probable carcinogen in a medication that is taken daily by adults and adolescents for a chronic condition like diabetes, makes [these findings] particularly troubling,” the pharmacy said in the petition. It noted that NDMA is classified by the World Health Organization and the International Agency for Research on Cancer as a Group 2A compound, meaning that it is “probably carcinogenic to humans.”
The Valisure findings are in contrast to those from the FDA’s own testing of metformin from eight companies. In results released Feb. 2, the agency found no NDMA in metformin from seven of the companies, and elevations within the safe limit in metformin from the remaining company. Based on those results, the FDA did not issue a recall.
The FDA declined to comment on the petition, pending a formal written response, a spokesman said.
Valisure said in its petition that one reason it found NDMA at concerning levels, and the FDA did not, could be that the pharmacy’s testing was more thorough than the agency’s because it had used its proprietary analytical technologies in addition to FDA standard assays. The pharmacy said it also cast a wider net, testing samples from 22 companies instead of 8, as the FDA had.
“At least one company that consistently displayed high levels of NDMA in all Valisure-tested batches was a company whose metformin products, to Valisure’s knowledge, were not tested by FDA,” Valisure said in the petition.
The pharmacy tested 38 batches of metformin from 22 companies, and found 16 contaminated batches from 11 companies. Results from one company were confirmed by an independent laboratory in California.
In addition, “there was significant variability from batch to batch, even within a single company, underscoring the importance of batch-level chemical analysis and the necessity of overall increased quality surveillance of medications,” the pharmacy stated in the petition.
David Light, Valisure founder and CEO, said in a press release that the results “indicate that contaminated batches of drugs are scattered and intermixed with clean [batches] throughout the American pharmaceutical supply chain. This strongly suggests that neither the limited testing FDA is able to conduct nor the pharmaceutical companies’ self-reporting of analytical results is sufficient to protect American consumers.”
He explained in an interview that metformin contamination probably comes from poor manufacturing, as NDMA can form during the manufacturing process. Companies are supposed to have processes in place to limit its formation and to check for and remove it before products are shipped. The contaminated batches might have come from China, which makes the bulk of U.S. active pharmaceutical ingredients, he said.
Recently, Apotex and Ranbaxy Pharmaceuticals recalled specific metformin lots in Canada after Canadian health authorities requested NDMA testing. Metformin versions have also been recalled in Singapore. European health authorities are also looking into the issue, according to a Mar. 3 press release from the European Medicines Agency.
Over the past 2 years, NDMA contamination has led to recalls of angiotensin receptor blockers, such as valsartan and losartan, because of NDMA in excess of the daily limit, and ranitidine-containing products such as Zantac. Valisure said it hopes the FDA will avoid the “year-long rolling recalls” that have occurred for angiotensin receptor blockers.
Metformin, which is used to treat type 2 diabetes, is the fourth-most prescribed drug in the United States. About 80 million prescriptions were written for it during 2019, according to the press release.
Valisure launched its investigation after it found NDMA in metformin a client asked it to check.
FDA rules to ban ESDs for self-injurious, aggressive behavior
The Food and Drug Administration has banned all electrical stimulation devices used for self-injurious or aggressive behavior because of an unreasonable risk of illness or injury. This marks only the third time the FDA has banned a medical device since it gained the authority to do so.
Electrical stimulation devices (ESDs) administer electric shocks through electrodes attached to the skin during self-injurious or aggressive behavior in an attempt to condition the patient to stop engaging in that behavior, according to the FDA press release. Current evidence indicates that use of these devices can lead to worsening of underlying symptoms, depression, anxiety, PTSD, pain, burns, and tissue damage; in contrast, evidence supporting their use is weak. In addition, many patients exposed to ESDs have intellectual or developmental disabilities and might not be able to adequately communicate their level of pain.
“Since ESDs were first marketed more than 20 years ago, we have gained a better understanding of the danger these devices present to public health. Through advancements in medical science, there are now more treatment options available to reduce or stop self-injurious or aggressive behavior, thus avoiding the substantial risk ESDs present,” William H. Maisel, MD, MPH, director of the Office of Product Evaluation and Quality in the FDA’s Center for Devices and Radiological Health, said in the release.
The ruling follows a 2016 proposal to ban ESDs from the marketplace; the proposed rule received more than 1,500 comments from stakeholders, such as parents of people with intellectual and developmental disabilities, state agencies and their sister public-private organizations, the affected manufacturer and residential facility, some of the facility’s employees, and parents of individual residents, as well as from state and federal legislators and advocacy groups. Nearly all supported the ban.
The rule will go into effect 30 days after publication of the rule in the Federal Register, and compliance is required within 180 days.
The Food and Drug Administration has banned all electrical stimulation devices used for self-injurious or aggressive behavior because of an unreasonable risk of illness or injury. This marks only the third time the FDA has banned a medical device since it gained the authority to do so.
Electrical stimulation devices (ESDs) administer electric shocks through electrodes attached to the skin during self-injurious or aggressive behavior in an attempt to condition the patient to stop engaging in that behavior, according to the FDA press release. Current evidence indicates that use of these devices can lead to worsening of underlying symptoms, depression, anxiety, PTSD, pain, burns, and tissue damage; in contrast, evidence supporting their use is weak. In addition, many patients exposed to ESDs have intellectual or developmental disabilities and might not be able to adequately communicate their level of pain.
“Since ESDs were first marketed more than 20 years ago, we have gained a better understanding of the danger these devices present to public health. Through advancements in medical science, there are now more treatment options available to reduce or stop self-injurious or aggressive behavior, thus avoiding the substantial risk ESDs present,” William H. Maisel, MD, MPH, director of the Office of Product Evaluation and Quality in the FDA’s Center for Devices and Radiological Health, said in the release.
The ruling follows a 2016 proposal to ban ESDs from the marketplace; the proposed rule received more than 1,500 comments from stakeholders, such as parents of people with intellectual and developmental disabilities, state agencies and their sister public-private organizations, the affected manufacturer and residential facility, some of the facility’s employees, and parents of individual residents, as well as from state and federal legislators and advocacy groups. Nearly all supported the ban.
The rule will go into effect 30 days after publication of the rule in the Federal Register, and compliance is required within 180 days.
The Food and Drug Administration has banned all electrical stimulation devices used for self-injurious or aggressive behavior because of an unreasonable risk of illness or injury. This marks only the third time the FDA has banned a medical device since it gained the authority to do so.
Electrical stimulation devices (ESDs) administer electric shocks through electrodes attached to the skin during self-injurious or aggressive behavior in an attempt to condition the patient to stop engaging in that behavior, according to the FDA press release. Current evidence indicates that use of these devices can lead to worsening of underlying symptoms, depression, anxiety, PTSD, pain, burns, and tissue damage; in contrast, evidence supporting their use is weak. In addition, many patients exposed to ESDs have intellectual or developmental disabilities and might not be able to adequately communicate their level of pain.
“Since ESDs were first marketed more than 20 years ago, we have gained a better understanding of the danger these devices present to public health. Through advancements in medical science, there are now more treatment options available to reduce or stop self-injurious or aggressive behavior, thus avoiding the substantial risk ESDs present,” William H. Maisel, MD, MPH, director of the Office of Product Evaluation and Quality in the FDA’s Center for Devices and Radiological Health, said in the release.
The ruling follows a 2016 proposal to ban ESDs from the marketplace; the proposed rule received more than 1,500 comments from stakeholders, such as parents of people with intellectual and developmental disabilities, state agencies and their sister public-private organizations, the affected manufacturer and residential facility, some of the facility’s employees, and parents of individual residents, as well as from state and federal legislators and advocacy groups. Nearly all supported the ban.
The rule will go into effect 30 days after publication of the rule in the Federal Register, and compliance is required within 180 days.