Pharmacy

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Pill production

Credit: FDA

The US Food and Drug Administration (FDA) has granted orphan designation for the histone deacetylase (HDAC) inhibitor pracinostat to treat acute myeloid leukemia (AML) and the proteasome inhibitor marizomib to treat multiple myeloma (MM).

Orphan designation is available for drugs that treat or prevent rare diseases affecting fewer than 200,000 people in the US.

The designation qualifies the sponsor of a drug for development incentives, including tax credits for qualified clinical testing, prescription drug user fee exemptions, and 7-year marketing exclusivity upon FDA approval.

About pracinostat

The oral HDAC inhibitor pracinostat has been tested in phase 1 and 2 trials of adult and pediatric patients with advanced hematologic disorders and solid tumors.

The drug has been generally well tolerated in more than 200 patients to date, according to the drug’s maker, MEI Pharma.

In a dose-escalation phase 1 trial, pracinostat demonstrated single-agent activity in elderly AML patients. Two of 14 patients (14%) achieved a complete remission, with responses persisting more than 206 days and 362 days.

Researchers are currently conducting a phase 2 trial of pracinostat in combination with azacitidine in elderly patients with newly diagnosed AML. Preliminary data from this trial are expected to be available by December 2014.

About marizomib

The proteasome inhibitor marizomib is under development for the treatment of MM and other malignancies.

Intravenous marizomib has been evaluated in more than 230 patients across 4 phase 1/2 studies, as a single agent or in combination with dexamethasone or an HDAC inhibitor.

Researchers are currently evaluating marizomib in combination with dexamethasone in an ongoing phase 2 trial of highly refractory MM patients, including those who are refractory to carfilzomib.

Marizomib is also being tested in combination with pomalidomide and dexamethasone in a phase 1/2 study of patients with relapsed and refractory MM.

The drug’s maker, Triphase Accelerator Corporation, is currently developing an oral formulation of marizomib.

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

Scientists say they’ve created a synthetic form of low-molecular-weight heparin (LMWH) that is both reversible and safe for patients with poor kidney function.

In the event of uncontrolled bleeding, this synthetic heparin can be reversed by an existing drug.

And the LMWH is cleared by the liver rather than the kidneys.

The team described their creation of the drug in Nature Chemical Biology.

“When doctors talk to me about the kind of heparin they want to use during and after surgery, they want it reversible, and they want it to not go through the kidneys,” said study author Jian Liu, PhD, of the University of North Carolina, Chapel Hill.

Dr Liu noted that up to 5% of patients receiving heparin experience some form of uncontrolled bleeding. Patients receiving unfractionated heparin are in less danger because there is an existing FDA-approved antidote available, protamine.

But protamine is not as effective in reversing LMWH. So Dr Liu and his colleagues tweaked the drug’s molecular structure so that protamine is able to deactivate LMWH.

The team used a chemo-enzymatic process to synthesize the LMWH, an approach they developed in research on a simpler anticoagulant published in Science in 2011. Synthesizing the LMWH allowed them to make improvements on the animal-derived form of the drug.

That form of LMWH is cleared from the body by the kidneys, which can make it unsuitable for patients with a weakened renal system. So the researchers made changes that allowed their LMWH to bind to receptors that clear it through the liver.

“If a person’s kidneys aren’t effectively clearing heparin from the blood, the drug stays active in the body for longer than expected,” said study author Nigel Key, MB ChB, also of the University of North Carolina.

“That can represent a potentially dangerous situation for the physician, pharmacist, and patient.”

LMWH did prove dangerous in 2008, when more than 80 people died and hundreds of others suffered adverse reactions to the drug. Authorities linked the problems to a contaminant in raw natural heparin from China.

“Whenever you mix the food chain and the drug chain together, you end up with potential for disaster,” said study author Robert Linhardt, PhD, of the Rensselaer Polytechnic Institute in Troy, New York.

“Whether it comes from contamination, adulteration, impurities like viruses or prions—any of those possibilities are much more likely when you make something in an uncontrolled environment. This is a drug that millions of people rely upon, and it’s important to develop a safe, synthetic alternative to the current supply chain.”

LMWH makes up more than half the US market for heparin. The researchers said the new version they created is a safe, economically viable alternative to the existing animal-derived supply.

“The pig stuff has served us well for 50 years and is very inexpensive, but if we cannot control the supply chain, we cannot ensure the safety of the drug,” Dr Liu said. “I am working for the day when synthetic heparin can be brewed in large laboratories at a low cost.”

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Prescription medications

Credit: Steven Harbour

The US Food and Drug Administration (FDA) has launched a program that allows certain companies to expedite the importation of drugs and drug ingredients.

Thirteen companies have been selected to take part in this 2-year program, called the Secure Supply Chain Pilot Program.

As the companies meet certain criteria, they are eligible to receive expedited entry for up to 5 drug products. These products can enter the US after electronic screening without undergoing human examination.

The FDA said its goal with this program is to allow the agency to focus its imports surveillance resources on preventing the entry of drugs that are most likely to compromise the quality and safety of the US drug supply.

The companies that have been accepted into the program are:

• AbbVie Inc.
• Allergan, Inc.
• Astellas U.S. Technologies, Inc.
• Bristol-Myers Squibb Company
• Celgene Corporation
• GE Healthcare Inc.
• GlaxoSmithKline LLC
• Merck Sharp & Dohme Corporation
• Mylan Pharmaceuticals Inc.
• Novartis Pharmaceuticals Corporation
• Pfizer, Inc.
• Teva Pharmaceutcials USA, Inc.
• Watson Laboratories, Inc.

Each of these companies met the participation conditions, including:

• Committing to comply with requirements of the Food, Drug, and Cosmetics Act (FDCA)
• Having a validated, secure supply chain protocol per the US Customs and Border Protection’s Customs-Trade Partnership Against Terrorism (C-TPAT) program
• Having a plan in place to quickly correct potential problems the FDA identifies regarding importation of specific products
• Having effective recall and corrective action plans in place
• Maintaining control over their drugs from the time of manufacture abroad through entry into the US.

Over the next 2 years, the FDA will evaluate whether this program enhances imported drug compliance with FDA regulations and the security of the drug supply chain. If the FDA deems the program effective, a more permanent program may be established and possibly extended to additional companies.

For more information, see the FDA’s notice about the program, published in the Federal Register last August.

Drug in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted full approval of omacetaxine mepesuccinate (Synribo) for the treatment of chronic myeloid leukemia (CML).

The drug received accelerated approval in October 2012 to treat adults with chronic phase (CP) or accelerated phase (AP) CML who were resistant to or could not tolerate 2 or more tyrosine kinase inhibitors (TKIs).

But additional clinical trial data were required before the FDA could grant the drug full approval.

Now, the agency has granted that approval based on the final analysis of two phase 2 trials.

The original approval of omacetaxine mepesuccinate was based on an analysis of combined data subsets from these trials. The pooled analysis included patients who had received 2 or more approved TKIs and, at a minimum, had evidence of resistance or intolerance to dasatinib and/or nilotinib.

Forty-seven percent of patients with CP CML and 63% of patients with AP CML had failed treatment with 3 TKIs—imatinib, dasatinib, and nilotinib. The majority of patients had also received other treatments, including hydroxyurea, interferon, and cytarabine.

Among CP patients, 18% (14/76) achieved a major cytogenetic response (MCyR). The mean time to MCyR onset was 3.5 months, and the median duration of MCyR was 12.5 months.

Among AP Patients, 14% (5/35) achieved a major hematologic response (MaHR). The mean time to MaHR onset was 2.3 months, and the median duration of MaHR was 4.7 months.

The most common adverse events for AP and CP patients (occurring in 20% or more) were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia.

Omacetaxine mepesuccinate is the first protein synthesis inhibitor for CML. Although the drug’s mechanism of action is not fully understood, it is known to prevent the production of Bcr-Abl and Mcl-1, which help drive CML.

For more details on omacetaxine mepesuccinate, see the full prescribing information.

Drug in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted full approval of omacetaxine mepesuccinate (Synribo) for the treatment of chronic myeloid leukemia (CML).

The drug received accelerated approval in October 2012 to treat adults with chronic phase (CP) or accelerated phase (AP) CML who were resistant to or could not tolerate 2 or more tyrosine kinase inhibitors (TKIs).

But additional clinical trial data were required before the FDA could grant the drug full approval.

Now, the agency has granted that approval based on the final analysis of two phase 2 trials.

The original approval of omacetaxine mepesuccinate was based on an analysis of combined data subsets from these trials. The pooled analysis included patients who had received 2 or more approved TKIs and, at a minimum, had evidence of resistance or intolerance to dasatinib and/or nilotinib.

Forty-seven percent of patients with CP CML and 63% of patients with AP CML had failed treatment with 3 TKIs—imatinib, dasatinib, and nilotinib. The majority of patients had also received other treatments, including hydroxyurea, interferon, and cytarabine.

Among CP patients, 18% (14/76) achieved a major cytogenetic response (MCyR). The mean time to MCyR onset was 3.5 months, and the median duration of MCyR was 12.5 months.

Among AP Patients, 14% (5/35) achieved a major hematologic response (MaHR). The mean time to MaHR onset was 2.3 months, and the median duration of MaHR was 4.7 months.

The most common adverse events for AP and CP patients (occurring in 20% or more) were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia.

Omacetaxine mepesuccinate is the first protein synthesis inhibitor for CML. Although the drug’s mechanism of action is not fully understood, it is known to prevent the production of Bcr-Abl and Mcl-1, which help drive CML.

For more details on omacetaxine mepesuccinate, see the full prescribing information.

Drug in vials

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted full approval of omacetaxine mepesuccinate (Synribo) for the treatment of chronic myeloid leukemia (CML).

The drug received accelerated approval in October 2012 to treat adults with chronic phase (CP) or accelerated phase (AP) CML who were resistant to or could not tolerate 2 or more tyrosine kinase inhibitors (TKIs).

But additional clinical trial data were required before the FDA could grant the drug full approval.

Now, the agency has granted that approval based on the final analysis of two phase 2 trials.

The original approval of omacetaxine mepesuccinate was based on an analysis of combined data subsets from these trials. The pooled analysis included patients who had received 2 or more approved TKIs and, at a minimum, had evidence of resistance or intolerance to dasatinib and/or nilotinib.

Forty-seven percent of patients with CP CML and 63% of patients with AP CML had failed treatment with 3 TKIs—imatinib, dasatinib, and nilotinib. The majority of patients had also received other treatments, including hydroxyurea, interferon, and cytarabine.

Among CP patients, 18% (14/76) achieved a major cytogenetic response (MCyR). The mean time to MCyR onset was 3.5 months, and the median duration of MCyR was 12.5 months.

Among AP Patients, 14% (5/35) achieved a major hematologic response (MaHR). The mean time to MaHR onset was 2.3 months, and the median duration of MaHR was 4.7 months.

The most common adverse events for AP and CP patients (occurring in 20% or more) were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia.

Omacetaxine mepesuccinate is the first protein synthesis inhibitor for CML. Although the drug’s mechanism of action is not fully understood, it is known to prevent the production of Bcr-Abl and Mcl-1, which help drive CML.

For more details on omacetaxine mepesuccinate, see the full prescribing information.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has again decided not to approve the anticoagulant rivaroxaban (Xarelto) for use in patients with acute coronary syndromes (ACS).

The drug’s developers are seeking approval of rivaroxaban to reduce the risk of secondary cardiovascular events—heart attack, stroke, or death—and to reduce the risk of stent thrombosis in ACS patients.

For both indications, the drug would be given in combination with standard antiplatelet therapy.

This is not the first time the FDA has decided against approving rivaroxaban for use in ACS patients. The agency rejected the drug as prophylaxis for cardiovascular events in June 2012 and March 2013. And the drug was denied approval for stent thrombosis in June 2013.

Nevertheless, it seems the companies developing rivaroxaban—Janssen Research & Development, LLC and Bayer HealthCare—plan to continue pursuing approvals for these indications.

“We remain committed to providing patients who have suffered from acute coronary syndrome with additional protection against stent thrombosis and secondary, life-threatening cardiovascular events,” said Paul Burton, MD, PhD, Vice President, Clinical Development, Janssen Research & Development.

“We are evaluating the contents of the [FDA’s complete response] letters and will determine the appropriate next steps.”

Both applications for expanding rivaroxaban use were based on results from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in November 2011.

The study showed that rivaroxaban, when given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients, compared to placebo. But rivaroxaban also increased the risk of major bleeding and intracranial hemorrhage.

In past evaluations of rivaroxaban, the FDA and its advisors expressed concerns about data from this trial, particularly the risk of bleeding associated with rivaroxaban and some gaps in trial data.

Although Janssen submitted the missing data, the FDA still had reservations about rivaroxaban’s safety and efficacy in ACS patients. The FDA recently suggested the company limit the proposed duration of rivaroxaban treatment, as the drug might be safer and more effective when given for a shorter period.

So Janssen changed the suggested treatment duration to 90 days. But last month, an FDA advisory committee still recommended against expanding the drug’s indication. And the agency seems to have taken that recommendation to heart.

Rivaroxaban is currently FDA-approved to treat patients with venous thromboembolism (VTE) and to reduce the risk of VTE recurrence following an initial 6-month treatment for acute VTE. The drug is also approved for use as thromboprophylaxis for patients with non-valvular atrial fibrillation, those who have undergone knee replacement surgery, and patients who have had hip replacement surgery.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has again decided not to approve the anticoagulant rivaroxaban (Xarelto) for use in patients with acute coronary syndromes (ACS).

The drug’s developers are seeking approval of rivaroxaban to reduce the risk of secondary cardiovascular events—heart attack, stroke, or death—and to reduce the risk of stent thrombosis in ACS patients.

For both indications, the drug would be given in combination with standard antiplatelet therapy.

This is not the first time the FDA has decided against approving rivaroxaban for use in ACS patients. The agency rejected the drug as prophylaxis for cardiovascular events in June 2012 and March 2013. And the drug was denied approval for stent thrombosis in June 2013.

Nevertheless, it seems the companies developing rivaroxaban—Janssen Research & Development, LLC and Bayer HealthCare—plan to continue pursuing approvals for these indications.

“We remain committed to providing patients who have suffered from acute coronary syndrome with additional protection against stent thrombosis and secondary, life-threatening cardiovascular events,” said Paul Burton, MD, PhD, Vice President, Clinical Development, Janssen Research & Development.

“We are evaluating the contents of the [FDA’s complete response] letters and will determine the appropriate next steps.”

Both applications for expanding rivaroxaban use were based on results from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in November 2011.

The study showed that rivaroxaban, when given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients, compared to placebo. But rivaroxaban also increased the risk of major bleeding and intracranial hemorrhage.

In past evaluations of rivaroxaban, the FDA and its advisors expressed concerns about data from this trial, particularly the risk of bleeding associated with rivaroxaban and some gaps in trial data.

Although Janssen submitted the missing data, the FDA still had reservations about rivaroxaban’s safety and efficacy in ACS patients. The FDA recently suggested the company limit the proposed duration of rivaroxaban treatment, as the drug might be safer and more effective when given for a shorter period.

So Janssen changed the suggested treatment duration to 90 days. But last month, an FDA advisory committee still recommended against expanding the drug’s indication. And the agency seems to have taken that recommendation to heart.

Rivaroxaban is currently FDA-approved to treat patients with venous thromboembolism (VTE) and to reduce the risk of VTE recurrence following an initial 6-month treatment for acute VTE. The drug is also approved for use as thromboprophylaxis for patients with non-valvular atrial fibrillation, those who have undergone knee replacement surgery, and patients who have had hip replacement surgery.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration (FDA) has again decided not to approve the anticoagulant rivaroxaban (Xarelto) for use in patients with acute coronary syndromes (ACS).

The drug’s developers are seeking approval of rivaroxaban to reduce the risk of secondary cardiovascular events—heart attack, stroke, or death—and to reduce the risk of stent thrombosis in ACS patients.

For both indications, the drug would be given in combination with standard antiplatelet therapy.

This is not the first time the FDA has decided against approving rivaroxaban for use in ACS patients. The agency rejected the drug as prophylaxis for cardiovascular events in June 2012 and March 2013. And the drug was denied approval for stent thrombosis in June 2013.

Nevertheless, it seems the companies developing rivaroxaban—Janssen Research & Development, LLC and Bayer HealthCare—plan to continue pursuing approvals for these indications.

“We remain committed to providing patients who have suffered from acute coronary syndrome with additional protection against stent thrombosis and secondary, life-threatening cardiovascular events,” said Paul Burton, MD, PhD, Vice President, Clinical Development, Janssen Research & Development.

“We are evaluating the contents of the [FDA’s complete response] letters and will determine the appropriate next steps.”

Both applications for expanding rivaroxaban use were based on results from the phase 3 ATLAS ACS 2 TIMI 51 trial, which were published in NEJM in November 2011.

The study showed that rivaroxaban, when given in combination with standard antiplatelet therapy, reduced the composite endpoint of cardiovascular death, myocardial infarction, and stroke in ACS patients, compared to placebo. But rivaroxaban also increased the risk of major bleeding and intracranial hemorrhage.

In past evaluations of rivaroxaban, the FDA and its advisors expressed concerns about data from this trial, particularly the risk of bleeding associated with rivaroxaban and some gaps in trial data.

Although Janssen submitted the missing data, the FDA still had reservations about rivaroxaban’s safety and efficacy in ACS patients. The FDA recently suggested the company limit the proposed duration of rivaroxaban treatment, as the drug might be safer and more effective when given for a shorter period.

So Janssen changed the suggested treatment duration to 90 days. But last month, an FDA advisory committee still recommended against expanding the drug’s indication. And the agency seems to have taken that recommendation to heart.

Rivaroxaban is currently FDA-approved to treat patients with venous thromboembolism (VTE) and to reduce the risk of VTE recurrence following an initial 6-month treatment for acute VTE. The drug is also approved for use as thromboprophylaxis for patients with non-valvular atrial fibrillation, those who have undergone knee replacement surgery, and patients who have had hip replacement surgery.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Patient consults with pharmacist

Credit: Rhoda Baer

The US Food and Drug Administration (FDA) has expanded the indication for the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica).

Last November, the drug gained accelerated approval as a “breakthrough therapy” for patients with mantle cell lymphoma who had received at least 1 prior therapy.

Now, ibrutinib has been granted accelerated approval to treat patients with chronic lymphocytic leukemia (CLL) who have received at least 1 prior therapy.

The accelerated approval process allows the FDA to approve a drug based on a surrogate or intermediate endpoint that is reasonably likely to predict clinical benefit. Both approvals of ibrutinib are based on observed benefits in overall response rates.

Ibrutinib also received priority review and orphan-product designation for CLL.

Trial results

The accelerated approval of ibrutinib is based on results of a phase 1b/2 study, which included 48 patients with relapsed or refractory CLL. The patients had been diagnosed an average of 6.7 years prior to study enrollment and had received 4 prior therapies.

All patients received 420 mg of ibrutinib orally until disease progression or the development of unacceptable toxicity.

The overall response rate was 58.3%, and all of these were partial responses. The median duration of response was not reached (range, 5.6 months to more than 24.2 months).

Study investigators have not established whether ibrutinib confers improvements in survival or disease-related symptoms.

The median treatment duration was 15.6 months. Ten percent of patients (n=5) discontinued treatment due to adverse events. Three of these patients developed infections, and 2 had subdural hematomas. Thirteen percent of patients experienced adverse events that led to dose reductions.

The most commonly occurring adverse events (all grades and grade 3/4, respectively) included thrombocytopenia (71%, 10%), diarrhea (63%, 4%), bruising (54%, 2%), neutropenia (54%, 27%), anemia (44%, 0%), upper respiratory tract infection (48%, 26%), fatigue (31%, 4%), musculoskeletal pain (27%, 6%), rash (27%, 0%), pyrexia (25%, 2%), constipation (23%, 2%), peripheral edema (23%, 0%), arthralgia (23%, 0%), nausea (21%, 2%), stomatitis (21%, 0%), sinusitis (21%, 6%), and dizziness (21%, 0%).

Ibrutinib is being developed and commercialized by Pharmacyclics and Janssen Biotech, Inc. For full prescribing information, visit http://www.imbruvica.com/downloads/Prescribing_Information.pdf.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

Prescription medications

Credit: CDC

Health Canada has approved pomalidomide (Pomalyst) for use in combination with dexamethasone to treat patients with relapsed or refractory multiple myeloma (MM).

Patients must have received at least 2 prior therapies, failed treatment with lenalidomide and bortezomib, and experienced disease progression while on their last treatment regimen.

Health Canada had given pomalidomide priority review status due to the unmet need of effective therapies for patients with aggressive MM.

“Until now, there have been no approved options for patients whose disease has progressed despite available treatments,” said Donna E. Reece, MD, of the Princess Margaret Cancer Centre in Toronto.

“With Pomalyst, we have a new option that extends periods of remission, is generally well-tolerated, and can be taken in the convenience of a patient’s home.”

Trial prompts approval

Health Canada based its approval of pomalidomide on findings from the MM-003 trial. Regulatory agencies in the United States and European Union, both of which approved pomalidomide last year, based their decisions on the results of this study as well.

The phase 3 trial included 455 patients with relapsed or refractory MM who had received a median of 5 prior treatment regimens.

Patients were randomized to receive pomalidomide plus low-dose dexamethasone (POM-LoDEX, n=302) or high-dose dexamethasone alone (HiDEX, n=153). The median follow-up was 10 months.

Researchers found that response and survival rates were superior in the POM-LoDEX arm, and rates of adverse events were largely similar between the 2 arms.

The overall response rate was 31% (n=95) in the POM-LoDEX arm and 10% (n=15) in the HiDEX arm. The median duration of response was 7.0 months and 6.1 months, respectively.

The median progression-free survival was 4.0 months in the POM-LoDEX arm and 1.9 months in the HiDEX arm (P<0.001). And the median overall survival was 12.7 months in the POM-LoDEX arm and 8.1 months in the HiDEX arm (P=0.028).

Patients in the POM-LoDEX arm experienced more grade 3/4 neutropenia than patients in the HiDEX arm. But rates of grade 3/4 anemia and thrombocytopenia were similar.

Rates of grade 3/4 non-hematologic toxicities were also comparable and included infection, pneumonia, hemorrhage, glucose intolerance, and fatigue. Other adverse events of note included venous thromboembolism and peripheral neuropathy, which occurred at similar rates in both arms.

These results were presented at the 2013 ASCO Annual Meeting and published in The Lancet Oncology in October.

Drug availability

Pomalidomide is expected to be commercially available in Canada in March.

The drug will be distributed through a risk-management program called RevAid, which was developed in 2008. By adding pomalidomide to the program, regulators are aiming to prevent fetal exposure to the drug because of its structural similarities to thalidomide, a known human teratogen.

Under the program, only prescribers and pharmacists registered with RevAid are able to prescribe and dispense pomalidomide. In addition, only those patients who are registered and meet all the conditions of the RevAid program will receive the drug.

Nurse hangs bags filled

with chemotherapy drugs

Credit: Bill Branson

A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.

They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.

Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.

The suggestions appear in a consensus statement published in Pediatrics.

“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.

He and his coauthors developed the following recommendations:

1. Support national polices—and develop new measures—to prevent drug shortages
2. Use drug supplies efficiently to reduce the likelihood of shortages
3. Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
4. Develop an improved clearinghouse for sharing drug shortage information
5. Explore the sharing of drug supplies among institutions
6. Develop strategies to engage stakeholders in the management of drug shortages.

For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.

The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.

Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.

“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”

Nurse hangs bags filled

with chemotherapy drugs

Credit: Bill Branson

A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.

They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.

Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.

The suggestions appear in a consensus statement published in Pediatrics.

“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.

He and his coauthors developed the following recommendations:

1. Support national polices—and develop new measures—to prevent drug shortages
2. Use drug supplies efficiently to reduce the likelihood of shortages
3. Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
4. Develop an improved clearinghouse for sharing drug shortage information
5. Explore the sharing of drug supplies among institutions
6. Develop strategies to engage stakeholders in the management of drug shortages.

For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.

The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.

Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.

“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”

Nurse hangs bags filled

with chemotherapy drugs

Credit: Bill Branson

A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.

They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.

Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.

The suggestions appear in a consensus statement published in Pediatrics.

“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.

He and his coauthors developed the following recommendations:

1. Support national polices—and develop new measures—to prevent drug shortages
2. Use drug supplies efficiently to reduce the likelihood of shortages
3. Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
4. Develop an improved clearinghouse for sharing drug shortage information
5. Explore the sharing of drug supplies among institutions
6. Develop strategies to engage stakeholders in the management of drug shortages.

For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.

The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.

Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.

“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”

Red blood cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.

Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.

Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.

Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).

Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.

Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.

Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).

Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.

The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.

There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.

Red blood cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.

Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.

Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.

Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).

Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.

Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.

Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).

Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.

The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.

There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.

Red blood cells

The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).

Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.

Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.

Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.

Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).

Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.

Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.

Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).

Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.

The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.

There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.

Prescription bottles

Credit: Steven Harbour

The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.

In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.

The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.

The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.

At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).

And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).

Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.

Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.

Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.

Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.

Prescription bottles

Credit: Steven Harbour

The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.

In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.

The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.

The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.

At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).

And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).

Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.

Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.

Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.

Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.

Prescription bottles

Credit: Steven Harbour

The phase 3 RESONATE study has been stopped early due to positive results in patients receiving ibrutinib.

In this trial, researchers compared the BTK inhibitor ibrutinib to the CD20-directed antibody ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

The study has ended early because 2 key endpoints were met—namely, ibrutinib significantly improved progression-free and overall survival rates.

The RESONATE study enrolled 391 patients with relapsed or refractory CLL or SLL with measurable nodal disease who were not eligible for treatment with purine-analog-based therapy. Patients had received at least 1 prior therapy.

The researchers randomized patients to receive 420 mg of ibrutinib orally once daily or intravenous doses of ofatumumab over the course of 24 weeks until disease progression or unacceptable toxicity.

At the planned interim analysis, ibrutinib had significantly improved progression-free survival (the primary endpoint) and overall survival (a secondary endpoint).

And the safety profile of ibrutinib was acceptable, according to the companies developing the drug (Pharmacyclics, Inc. and Janssen Research and Development, LLC).

Based on these results, an independent data monitoring committee recommended that patients in the ofatumumab arm be given access to ibrutinib.

Pharmacyclics has informed the US Food and Drug Administration of this recommendation, and Janssen has informed the European Medicines Agency. Both companies are in talks with the health authorities to define the next regulatory steps.

Pharmacyclics has said detailed data from the RESONATE study will be presented at an upcoming oncology conference.

Ibrutinib was recently approved by the US Food and Drug Administration to treat mantle cell lymphoma.