Pharmacy

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

Micrograph showing ALL

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for an oral formulation of methotrexate (Jylamvo) as a treatment for acute lymphoblastic leukemia (ALL) and other disorders.

Jylamvo is a hybrid medicine of Methotrexat “Lederle” 25 mg-Stechampulle and Methotrexate “Lederle” 2.5 mg tablets, which have been authorized in the European Union since 1984 and 1959, respectively.

Jylamvo contains the same active substance as these reference medicines—the antineoplastic and immunomodulating agent methotrexate—but is given by mouth as a solution (2 mg/mL).

Jylamvo is intended for use as maintenance treatment in ALL patients age 3 and older.

The drug is also intended to treat:

• Active rheumatoid arthritis in adults
• Polyarthritic forms of active, severe juvenile idiopathic arthritis in adolescents and children age 3 and older when the response to non-steroidal anti-inflammatory drugs has been inadequate
• Severe, treatment-refractory, disabling psoriasis that does not respond sufficiently to other forms of treatment (such as phototherapy, retinoids, and psoralen and ultraviolet A radiation therapy) and severe psoriatic arthritis in adults.

The applicant for Jylamvo is Therakind Limited. Applications for hybrid medicines rely, in part, on the results of preclinical tests and clinical trials for a reference product and, in part, on new data.

The CHMP said studies have demonstrated the satisfactory quality of Jylamvo and its bioequivalence to Methotrexate “Lederle” 2.5 mg tablets and a third product, Ebetrexat 10 mg tablets, which is authorized for similar indications.

The CHMP has proposed that Jylamvo be prescribed by physicians with experience of the various properties of the medicinal product and its mode of action.

Detailed recommendations for the use of Jylamvo will be described in the summary of product characteristics, which will be published in the European public assessment report and made available in all official European Union languages if the European Commission grants marketing authorization for Jylamvo.

The European Commission typically makes a decision on a product within 67 days of the time the CHMP adopts its opinion.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab), an anti-CD20 monoclonal antibody, and TGR-1202, a PI3K delta inhibitor, in the treatment of diffuse large B-cell lymphoma (DLBCL).

The combination is currently being evaluated in patients with relapsed or refractory DLBCL in the phase 2b UNITY-DLBCL trial.

Ublituximab and TGR-1202 are both products of TG Therapeutics, Inc.

Updated results from a phase 1 study of ublituximab and TGR-1202 in patients with DLBCL and other malignancies were presented at the 21st Congress of the European Hematology Association.

The data included 165 patients treated with varying doses of TGR-1202 alone (n=90) or in combination with ublituximab (n=75). The patients were heavily pretreated, with the majority having 3 or more prior lines of therapy.

There were 7 evaluable patients with DLBCL who received the combination at the phase 3 doses— ublituximab at 900 mg and TGR-1202 at 800 mg micronized.

The overall response rate for this group was 57%. Of the 4 responders, 1 patient had a complete response, and 3 had a partial response. Two patients had stable disease, and 1 progressed.

In the overall study population, the most common adverse events were diarrhea (47%), nausea (45%), fatigue (37%), vomiting (27%), and neutropenia (21%). The most common grade 3/4 adverse events were neutropenia (18%) and anemia (5%).

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to

treat, diagnose, or prevent rare diseases/disorders affecting fewer than

200,000 people in the US.

Orphan designation provides companies

with certain incentives to develop products for rare diseases. This

includes a 50% tax break on research and development, a fee waiver,

access to federal grants, and 7 years of market exclusivity if the

product is approved.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab), an anti-CD20 monoclonal antibody, and TGR-1202, a PI3K delta inhibitor, in the treatment of diffuse large B-cell lymphoma (DLBCL).

The combination is currently being evaluated in patients with relapsed or refractory DLBCL in the phase 2b UNITY-DLBCL trial.

Ublituximab and TGR-1202 are both products of TG Therapeutics, Inc.

Updated results from a phase 1 study of ublituximab and TGR-1202 in patients with DLBCL and other malignancies were presented at the 21st Congress of the European Hematology Association.

The data included 165 patients treated with varying doses of TGR-1202 alone (n=90) or in combination with ublituximab (n=75). The patients were heavily pretreated, with the majority having 3 or more prior lines of therapy.

There were 7 evaluable patients with DLBCL who received the combination at the phase 3 doses— ublituximab at 900 mg and TGR-1202 at 800 mg micronized.

The overall response rate for this group was 57%. Of the 4 responders, 1 patient had a complete response, and 3 had a partial response. Two patients had stable disease, and 1 progressed.

In the overall study population, the most common adverse events were diarrhea (47%), nausea (45%), fatigue (37%), vomiting (27%), and neutropenia (21%). The most common grade 3/4 adverse events were neutropenia (18%) and anemia (5%).

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to

treat, diagnose, or prevent rare diseases/disorders affecting fewer than

200,000 people in the US.

Orphan designation provides companies

with certain incentives to develop products for rare diseases. This

includes a 50% tax break on research and development, a fee waiver,

access to federal grants, and 7 years of market exclusivity if the

product is approved.

Micrograph showing DLBCL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab), an anti-CD20 monoclonal antibody, and TGR-1202, a PI3K delta inhibitor, in the treatment of diffuse large B-cell lymphoma (DLBCL).

The combination is currently being evaluated in patients with relapsed or refractory DLBCL in the phase 2b UNITY-DLBCL trial.

Ublituximab and TGR-1202 are both products of TG Therapeutics, Inc.

Updated results from a phase 1 study of ublituximab and TGR-1202 in patients with DLBCL and other malignancies were presented at the 21st Congress of the European Hematology Association.

The data included 165 patients treated with varying doses of TGR-1202 alone (n=90) or in combination with ublituximab (n=75). The patients were heavily pretreated, with the majority having 3 or more prior lines of therapy.

There were 7 evaluable patients with DLBCL who received the combination at the phase 3 doses— ublituximab at 900 mg and TGR-1202 at 800 mg micronized.

The overall response rate for this group was 57%. Of the 4 responders, 1 patient had a complete response, and 3 had a partial response. Two patients had stable disease, and 1 progressed.

In the overall study population, the most common adverse events were diarrhea (47%), nausea (45%), fatigue (37%), vomiting (27%), and neutropenia (21%). The most common grade 3/4 adverse events were neutropenia (18%) and anemia (5%).

About orphan designation

The FDA grants orphan designation to drugs and biologics intended to

treat, diagnose, or prevent rare diseases/disorders affecting fewer than

200,000 people in the US.

Orphan designation provides companies

with certain incentives to develop products for rare diseases. This

includes a 50% tax break on research and development, a fee waiver,

access to federal grants, and 7 years of market exclusivity if the

product is approved.

Lenalidomide (Revlimid®)
Photo courtesy of Celgene

Health Canada has expanded the approved indication for lenalidomide (Revlimid®) to include the treatment of patients with multiple myeloma (MM).

Lenalidomide is now approved for use in combination with dexamethasone to treat patients newly diagnosed with MM who are not eligible for stem cell transplant.

Lenalidomide was previously approved in Canada for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality, with or without additional cytogenetic abnormalities.

Lenalidomide is a product of Celgene Corporation.

“The expanded indication of Revlimid® provides [MM] patients with a treatment much earlier in their disease and offers this patient population an all-oral, melphalan-free option for a disease that continues to be difficult to treat,” said Donna Reece, MD, of Princess Margaret Hospital in Toronto, Ontario, Canada.

The expanded approval of lenalidomide is based on safety and efficacy results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology last November.

The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.

Patients were randomized to receive:

• Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535)
• 18 cycles of Rd (Rd18) for 72 weeks (n=541)
• Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median progression-free survival (PFS) was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rates were 33%, 14%, and 13%, respectively.

The median overall survival (OS) was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rates were 60%, 57%, and 51%, respectively.

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

“With this new clinical evidence, we know that keeping newly diagnosed multiple myeloma patients on Revlimid® may help delay disease progression and reduce the risk of death,” Dr Reece said. “As such, we are looking forward to having Revlimid® as a key option in the first-line setting for the appropriate patients.”

Lenalidomide (Revlimid®)
Photo courtesy of Celgene

Health Canada has expanded the approved indication for lenalidomide (Revlimid®) to include the treatment of patients with multiple myeloma (MM).

Lenalidomide is now approved for use in combination with dexamethasone to treat patients newly diagnosed with MM who are not eligible for stem cell transplant.

Lenalidomide was previously approved in Canada for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality, with or without additional cytogenetic abnormalities.

Lenalidomide is a product of Celgene Corporation.

“The expanded indication of Revlimid® provides [MM] patients with a treatment much earlier in their disease and offers this patient population an all-oral, melphalan-free option for a disease that continues to be difficult to treat,” said Donna Reece, MD, of Princess Margaret Hospital in Toronto, Ontario, Canada.

The expanded approval of lenalidomide is based on safety and efficacy results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology last November.

The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.

Patients were randomized to receive:

• Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535)
• 18 cycles of Rd (Rd18) for 72 weeks (n=541)
• Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median progression-free survival (PFS) was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rates were 33%, 14%, and 13%, respectively.

The median overall survival (OS) was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rates were 60%, 57%, and 51%, respectively.

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

“With this new clinical evidence, we know that keeping newly diagnosed multiple myeloma patients on Revlimid® may help delay disease progression and reduce the risk of death,” Dr Reece said. “As such, we are looking forward to having Revlimid® as a key option in the first-line setting for the appropriate patients.”

Lenalidomide (Revlimid®)
Photo courtesy of Celgene

Health Canada has expanded the approved indication for lenalidomide (Revlimid®) to include the treatment of patients with multiple myeloma (MM).

Lenalidomide is now approved for use in combination with dexamethasone to treat patients newly diagnosed with MM who are not eligible for stem cell transplant.

Lenalidomide was previously approved in Canada for the treatment of patients with transfusion-dependent anemia due to low- or intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality, with or without additional cytogenetic abnormalities.

Lenalidomide is a product of Celgene Corporation.

“The expanded indication of Revlimid® provides [MM] patients with a treatment much earlier in their disease and offers this patient population an all-oral, melphalan-free option for a disease that continues to be difficult to treat,” said Donna Reece, MD, of Princess Margaret Hospital in Toronto, Ontario, Canada.

The expanded approval of lenalidomide is based on safety and efficacy results from the phase 3 FIRST trial. Updated results from this study were published in the Journal of Clinical Oncology last November.

The trial included 1623 patients with newly diagnosed MM who were not eligible for stem cell transplant.

Patients were randomized to receive:

• Lenalidomide and low-dose dexamethasone (Rd) in 28-day cycles until disease progression (n=535)
• 18 cycles of Rd (Rd18) for 72 weeks (n=541)
• Melphalan, prednisone, and thalidomide (MPT) for 72 weeks (n=547).

In the intent-to-treat population, the overall response rate was 81% for the continuous Rd group, 79% for the Rd18 group, and 67% in the MPT group. The complete response rates were 21%, 20%, and 12%, respectively.

The median progression-free survival (PFS) was 26.0 months in the continuous Rd group, 21.0 months in the Rd18 group, and 21.9 months in the MPT group. At 4 years, the PFS rates were 33%, 14%, and 13%, respectively.

The median overall survival (OS) was 58.9 months in the continuous Rd group, 56.7 months in the Rd18 group, and 48.5 months in the MPT group. At 4 years, the OS rates were 60%, 57%, and 51%, respectively.

The most frequent grade 3/4 hematologic treatment-emergent adverse events were neutropenia and anemia. The rate of grade 3/4 neutropenia was higher in the MPT group than the continuous Rd or Rd18 groups.

Infections were the most common grade 3/4 non-hematologic treatment-emergent adverse events. The rate of grade 3/4 infections was higher in the Rd groups than the MPT group.

“With this new clinical evidence, we know that keeping newly diagnosed multiple myeloma patients on Revlimid® may help delay disease progression and reduce the risk of death,” Dr Reece said. “As such, we are looking forward to having Revlimid® as a key option in the first-line setting for the appropriate patients.”

Pills

The European Medicines Agency (EMA) has released a report showing both successes and room for improvement regarding conditional marketing authorizations (CMAs).

CMA is one of the tools available to regulators to support the development of and early access to drugs that address unmet medical needs of patients in the European Union.

Drugs are granted CMA if the public health benefit of their immediate availability is thought to outweigh the risk of an authorization on the basis of less comprehensive data than normally required.

A CMA is valid for 1 year. As part of the authorization, the drug’s developer is obliged to carry out further studies to obtain complete data.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) assesses the data generated by these specific post-authorization obligations at least annually to ensure the balance of benefits and risks of the drug continues to remain positive.

At the end of its assessment, the CHMP issues a recommendation regarding the renewal of the CMA or its conversion into a standard marketing authorization.

Overview

The EMA’s report summarizes the experience with CMAs from the first use of this authorization type in 2006 until June 30, 2016.

During this time, a total of 30 drugs have received a CMA, including several

hematology drugs—Adcetris (brentuximab vedotin),

Arzerra (ofatumumab), Blincyto (blinatumomab), Bosulif (bosutinib), Darzalex (daratumumab), and Pixuvri (pixantrone).

Eleven CMAs have been converted into standard marketing authorizations (including Arzerra’s CMA), 2 have been withdrawn for commercial reasons, and 17 are still conditional authorizations.

None of the drugs that still have CMAs have been authorized for more than 5 years. And none of the CMAs issued since 2006 have had to be revoked or suspended.

Successes

According to the EMA’s analysis, marketing authorization holders comply with the specific obligations imposed by the agency.

More than 90% of completed specific obligations did not result in major changes of scope, and about 70% of specific obligations did not require an extension to the originally specified timelines.

The report shows that it took an average of 4 years to generate the additional data needed and to convert a CMA into a full marketing authorization.

This suggests patients with life-threatening or seriously debilitating conditions had access to promising drugs much earlier than they would have under standard authorization.

Areas for improvement

The EMA’s analysis also revealed room for improvement.

The report showed that, relatively frequently, CMA was first

considered only during the assessment of the drug application, which meant granting a CMA took longer than intended.

Therefore, the EMA recommends that drug developers engage in early dialogue with the EMA

and prospectively plan to apply for a CMA.

The agency said this should support

prompt assessment of such applications and could also facilitate prompt

completion of additional studies and timely availability of

comprehensive data.

The EMA said another area for improvement is engaging other stakeholders involved in bringing drugs to patients—in particular, Health Technology Assessment bodies—to facilitate the generation of all data needed for decision-making through one development program.

Pills

The European Medicines Agency (EMA) has released a report showing both successes and room for improvement regarding conditional marketing authorizations (CMAs).

CMA is one of the tools available to regulators to support the development of and early access to drugs that address unmet medical needs of patients in the European Union.

Drugs are granted CMA if the public health benefit of their immediate availability is thought to outweigh the risk of an authorization on the basis of less comprehensive data than normally required.

A CMA is valid for 1 year. As part of the authorization, the drug’s developer is obliged to carry out further studies to obtain complete data.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) assesses the data generated by these specific post-authorization obligations at least annually to ensure the balance of benefits and risks of the drug continues to remain positive.

At the end of its assessment, the CHMP issues a recommendation regarding the renewal of the CMA or its conversion into a standard marketing authorization.

Overview

The EMA’s report summarizes the experience with CMAs from the first use of this authorization type in 2006 until June 30, 2016.

During this time, a total of 30 drugs have received a CMA, including several

hematology drugs—Adcetris (brentuximab vedotin),

Arzerra (ofatumumab), Blincyto (blinatumomab), Bosulif (bosutinib), Darzalex (daratumumab), and Pixuvri (pixantrone).

Eleven CMAs have been converted into standard marketing authorizations (including Arzerra’s CMA), 2 have been withdrawn for commercial reasons, and 17 are still conditional authorizations.

None of the drugs that still have CMAs have been authorized for more than 5 years. And none of the CMAs issued since 2006 have had to be revoked or suspended.

Successes

According to the EMA’s analysis, marketing authorization holders comply with the specific obligations imposed by the agency.

More than 90% of completed specific obligations did not result in major changes of scope, and about 70% of specific obligations did not require an extension to the originally specified timelines.

The report shows that it took an average of 4 years to generate the additional data needed and to convert a CMA into a full marketing authorization.

This suggests patients with life-threatening or seriously debilitating conditions had access to promising drugs much earlier than they would have under standard authorization.

Areas for improvement

The EMA’s analysis also revealed room for improvement.

The report showed that, relatively frequently, CMA was first

considered only during the assessment of the drug application, which meant granting a CMA took longer than intended.

Therefore, the EMA recommends that drug developers engage in early dialogue with the EMA

and prospectively plan to apply for a CMA.

The agency said this should support

prompt assessment of such applications and could also facilitate prompt

completion of additional studies and timely availability of

comprehensive data.

The EMA said another area for improvement is engaging other stakeholders involved in bringing drugs to patients—in particular, Health Technology Assessment bodies—to facilitate the generation of all data needed for decision-making through one development program.

Pills

The European Medicines Agency (EMA) has released a report showing both successes and room for improvement regarding conditional marketing authorizations (CMAs).

CMA is one of the tools available to regulators to support the development of and early access to drugs that address unmet medical needs of patients in the European Union.

Drugs are granted CMA if the public health benefit of their immediate availability is thought to outweigh the risk of an authorization on the basis of less comprehensive data than normally required.

A CMA is valid for 1 year. As part of the authorization, the drug’s developer is obliged to carry out further studies to obtain complete data.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) assesses the data generated by these specific post-authorization obligations at least annually to ensure the balance of benefits and risks of the drug continues to remain positive.

At the end of its assessment, the CHMP issues a recommendation regarding the renewal of the CMA or its conversion into a standard marketing authorization.

Overview

The EMA’s report summarizes the experience with CMAs from the first use of this authorization type in 2006 until June 30, 2016.

During this time, a total of 30 drugs have received a CMA, including several

hematology drugs—Adcetris (brentuximab vedotin),

Arzerra (ofatumumab), Blincyto (blinatumomab), Bosulif (bosutinib), Darzalex (daratumumab), and Pixuvri (pixantrone).

Eleven CMAs have been converted into standard marketing authorizations (including Arzerra’s CMA), 2 have been withdrawn for commercial reasons, and 17 are still conditional authorizations.

None of the drugs that still have CMAs have been authorized for more than 5 years. And none of the CMAs issued since 2006 have had to be revoked or suspended.

Successes

According to the EMA’s analysis, marketing authorization holders comply with the specific obligations imposed by the agency.

More than 90% of completed specific obligations did not result in major changes of scope, and about 70% of specific obligations did not require an extension to the originally specified timelines.

The report shows that it took an average of 4 years to generate the additional data needed and to convert a CMA into a full marketing authorization.

This suggests patients with life-threatening or seriously debilitating conditions had access to promising drugs much earlier than they would have under standard authorization.

Areas for improvement

The EMA’s analysis also revealed room for improvement.

The report showed that, relatively frequently, CMA was first

considered only during the assessment of the drug application, which meant granting a CMA took longer than intended.

Therefore, the EMA recommends that drug developers engage in early dialogue with the EMA

and prospectively plan to apply for a CMA.

The agency said this should support

prompt assessment of such applications and could also facilitate prompt

completion of additional studies and timely availability of

comprehensive data.

The EMA said another area for improvement is engaging other stakeholders involved in bringing drugs to patients—in particular, Health Technology Assessment bodies—to facilitate the generation of all data needed for decision-making through one development program.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Ibrutinib (Imbruvica)
Photo courtesy of
Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has approved the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica®) for the treatment of marginal zone lymphoma (MZL).

The drug is now approved to treat patients with relapsed/refractory MZL who require systemic therapy and have received at least 1 prior anti-CD20-based therapy.

Ibrutinib has accelerated approval for this indication, based on the overall response rate the drug produced in a phase 2 trial.

Continued approval of ibrutinib as a treatment for MZL may be contingent upon verification and description of clinical benefit in a confirmatory trial.

The FDA’s approval of ibrutinib for MZL makes it the first treatment approved specifically for patients with this disease. It also marks the seventh FDA approval and fifth disease indication for ibrutinib since the drug was first approved in 2013.

Ibrutinib is also FDA-approved to treat chronic lymphocytic leukemia/small lymphocytic lymphoma, patients with mantle cell lymphoma who have received at least 1 prior therapy, and patients with Waldenström’s macroglobulinemia. The approval for mantle cell lymphoma is an accelerated approval.

Ibrutinib is jointly developed and commercialized by Pharmacyclics LLC, an AbbVie company, and Janssen Biotech, Inc.

Phase 2 trial

The FDA’s approval of ibrutinib for MZL is based on data from the phase 2, single-arm PCYC-1121 study, in which researchers evaluated the drug in MZL patients who required systemic therapy and had received at least 1 prior anti-CD20-based therapy.

Results from this study were presented at the 2016 ASH Annual Meeting (abstract 1213).

The efficacy analysis included 63 patients with 3 subtypes of MZL: mucosa-associated lymphoid tissue (n=32), nodal (n=17), and splenic (n=14).

The overall response rate was 46%, with a partial response rate of 42.9% and a complete response rate of 3.2%. Responses were observed across all 3 MZL subtypes.

The median time to response was 4.5 months (range, 2.3-16.4 months). And the median duration of response was not reached (range, 16.7 months to not reached).

Overall, the safety data from this study was consistent with the known safety profile of ibrutinib in B-cell malignancies.

The most common adverse events of all grades (occurring in >20% of patients) were thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%).

The most common (>10%) grade 3 or 4 events were decreases in hemoglobin and neutrophils (13% each) and pneumonia (10%).

The risks associated with ibrutinib as listed in the Warnings and Precautions section of the prescribing information are hemorrhage, infections, cytopenias, atrial fibrillation, hypertension, secondary primary malignancies, tumor lysis syndrome, and embryo fetal toxicities.

Drug production
Photo courtesy of the FDA

An investigation by Kaiser Health News (KHN) suggests some pharmaceutical companies are using the Orphan Drug Act to create monopolies and charge high prices for drugs that are already approved for mass market use in the US.

The US Food and Drug Administration (FDA) grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent conditions that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

However, the KHN investigation showed that some companies have been applying for—and obtaining—orphan designation for drugs already used to treat large populations.

The report states that more than 70 drugs that currently have orphan status were first approved by the FDA for mass market use.

In fact, 7 of the 10 best-selling drugs of 2015 were also orphan drugs. Included on this list are Rituxan (rituximab), Neulasta (pegfilgrastim), and Revlimid (lenalidomide).

The report also states that more than 80 drugs with orphan designation have been approved to treat more than one rare disease. For example, Gleevec (imatinib) has 9 orphan designations.

The KHN investigation revealed that, overall, about a third of orphan designations granted since the Orphan Drug Act was passed in 1983 have been either for repurposed mass market drugs or drugs that received multiple orphan designations. (Roughly 450 orphan drugs have been brought to market since 1983, according to the report.)

For each orphan designation, a drug’s developer qualifies for “a fresh batch of incentives,” the report notes.

The exclusivity incentive means the FDA won’t approve another version of an orphan drug to treat the rare disease(s) in question for 7 years, even if the company’s patent on the brand-name drug has expired.

For example, generic versions of imatinib are being used to treat chronic myeloid leukemia in the US because the patent for Gleevec has expired. However, because of an orphan designation, Novartis still has exclusivity for Gleevec (and will until 2020) as a treatment for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia who are also on chemotherapy.

The KHN report notes that exclusivity can be “a potent pricing tool” due to a lack of competition. And this means orphan drugs may “come with astronomical price tags.”

For instance, there are 33 orphan drugs that cost at least $28,000 for a 30-day supply and 4 orphan drugs that cost more than $70,000 per month.

According to the KHN report, the FDA is planning to investigate this issue.

Gayatri Rao, MD, director of the FDA’s Office of Orphan Products Development, has asked for a review of all orphan designations granted in 2010 and 2015. She said the review will not extend further because the FDA does not have the resources to review all orphan drugs.

Drug production
Photo courtesy of the FDA

An investigation by Kaiser Health News (KHN) suggests some pharmaceutical companies are using the Orphan Drug Act to create monopolies and charge high prices for drugs that are already approved for mass market use in the US.

The US Food and Drug Administration (FDA) grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent conditions that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

However, the KHN investigation showed that some companies have been applying for—and obtaining—orphan designation for drugs already used to treat large populations.

The report states that more than 70 drugs that currently have orphan status were first approved by the FDA for mass market use.

In fact, 7 of the 10 best-selling drugs of 2015 were also orphan drugs. Included on this list are Rituxan (rituximab), Neulasta (pegfilgrastim), and Revlimid (lenalidomide).

The report also states that more than 80 drugs with orphan designation have been approved to treat more than one rare disease. For example, Gleevec (imatinib) has 9 orphan designations.

The KHN investigation revealed that, overall, about a third of orphan designations granted since the Orphan Drug Act was passed in 1983 have been either for repurposed mass market drugs or drugs that received multiple orphan designations. (Roughly 450 orphan drugs have been brought to market since 1983, according to the report.)

For each orphan designation, a drug’s developer qualifies for “a fresh batch of incentives,” the report notes.

The exclusivity incentive means the FDA won’t approve another version of an orphan drug to treat the rare disease(s) in question for 7 years, even if the company’s patent on the brand-name drug has expired.

For example, generic versions of imatinib are being used to treat chronic myeloid leukemia in the US because the patent for Gleevec has expired. However, because of an orphan designation, Novartis still has exclusivity for Gleevec (and will until 2020) as a treatment for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia who are also on chemotherapy.

The KHN report notes that exclusivity can be “a potent pricing tool” due to a lack of competition. And this means orphan drugs may “come with astronomical price tags.”

For instance, there are 33 orphan drugs that cost at least $28,000 for a 30-day supply and 4 orphan drugs that cost more than $70,000 per month.

According to the KHN report, the FDA is planning to investigate this issue.

Gayatri Rao, MD, director of the FDA’s Office of Orphan Products Development, has asked for a review of all orphan designations granted in 2010 and 2015. She said the review will not extend further because the FDA does not have the resources to review all orphan drugs.

Drug production
Photo courtesy of the FDA

An investigation by Kaiser Health News (KHN) suggests some pharmaceutical companies are using the Orphan Drug Act to create monopolies and charge high prices for drugs that are already approved for mass market use in the US.

The US Food and Drug Administration (FDA) grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent conditions that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This includes a 50% tax break on research and development, a fee waiver, access to federal grants, and 7 years of market exclusivity if the product is approved.

However, the KHN investigation showed that some companies have been applying for—and obtaining—orphan designation for drugs already used to treat large populations.

The report states that more than 70 drugs that currently have orphan status were first approved by the FDA for mass market use.

In fact, 7 of the 10 best-selling drugs of 2015 were also orphan drugs. Included on this list are Rituxan (rituximab), Neulasta (pegfilgrastim), and Revlimid (lenalidomide).

The report also states that more than 80 drugs with orphan designation have been approved to treat more than one rare disease. For example, Gleevec (imatinib) has 9 orphan designations.

The KHN investigation revealed that, overall, about a third of orphan designations granted since the Orphan Drug Act was passed in 1983 have been either for repurposed mass market drugs or drugs that received multiple orphan designations. (Roughly 450 orphan drugs have been brought to market since 1983, according to the report.)

For each orphan designation, a drug’s developer qualifies for “a fresh batch of incentives,” the report notes.

The exclusivity incentive means the FDA won’t approve another version of an orphan drug to treat the rare disease(s) in question for 7 years, even if the company’s patent on the brand-name drug has expired.

For example, generic versions of imatinib are being used to treat chronic myeloid leukemia in the US because the patent for Gleevec has expired. However, because of an orphan designation, Novartis still has exclusivity for Gleevec (and will until 2020) as a treatment for patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia who are also on chemotherapy.

The KHN report notes that exclusivity can be “a potent pricing tool” due to a lack of competition. And this means orphan drugs may “come with astronomical price tags.”

For instance, there are 33 orphan drugs that cost at least $28,000 for a 30-day supply and 4 orphan drugs that cost more than $70,000 per month.

According to the KHN report, the FDA is planning to investigate this issue.

Gayatri Rao, MD, director of the FDA’s Office of Orphan Products Development, has asked for a review of all orphan designations granted in 2010 and 2015. She said the review will not extend further because the FDA does not have the resources to review all orphan drugs.

Vials of drugs
Photo by Bill Branson

The US Food and Drug Administration (FDA) has released 3 new draft guidance documents for industry.

One document provides an overview of scientific considerations when attempting to demonstrate that a biosimilar product is interchangeable with a reference product.

The other 2 guidance documents are intended to clarify the FDA’s position regarding communications about medical products.

The first draft guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” is intended to assist applicants in demonstrating that a proposed therapeutic protein product (eg, monoclonal antibodies) is interchangeable with a reference product under section 351(k) of the Public Health Service Act.

An interchangeable biological product is biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient. 

For a biological product that is administered more than once, the risk in terms of safety or diminished efficacy of alternating or switching between the biological product and the reference product must not be greater than the risk of using the reference product without such alternating/switching.

The approval pathway for biosimilar and interchangeable products was established by the Biologics Price Competition and Innovation Act of 2009, which was enacted as part of the Affordable Care Act in March 2010.

The FDA’s draft guidance on biosimilars contains information on:

• Factors impacting the type and amount of data and information needed to support a demonstration of interchangeability
• The data and information needed to support a demonstration of interchangeability
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
• Recommendations regarding the use of US-licensed reference products in a switching study or studies
• Considerations for developing presentations (eg, container closure systems) for proposed interchangeable products.

In addition to soliciting comments on this draft guidance, the FDA is inviting comments on questions posed in the notice of availability about interchangeability in general, the regulation of interchangeable products over their life cycle, and questions about considerations regarding post-approval manufacturing changes. 

The FDA also released a Center for Drug Evaluation and Research “From Our Perspective,” by Leah Christl, describing aspects of this draft guidance.

For more information on how to submit comments on the draft guidance and questions posed in the notice of availability, see the Federal Register notice.

Medical communications

The FDA also released 2 draft guidance documents that, the agency says, will each help provide clarity for medical product companies, as well as other interested parties, on the FDA’s current thinking and recommendations for a few different types of communications about medical products.

The first draft guidance, “Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities,” explains the FDA’s current thinking and recommendations on firms’ communication of healthcare economic information about approved drugs under section 502(a) of the Federal Food, Drug, and Cosmetic Act, which was recently amended by the 21st Century Cures Act. 

The guidance also answers common questions and provides the FDA’s recommendations regarding firms’ communications to payors about investigational drugs and devices that are not yet approved or cleared for any use.

The second draft guidance, “Medical Product Communications That Are Consistent With the FDA-Required Labeling,” explains the FDA’s current thinking about firms’ medical product communications that include data and information that are not contained in their products’ FDA-required labeling, but that concern the approved or cleared uses of their products.

The FDA has opened a public comment period for each draft guidance.

The agency is also asking for stakeholder input on another, distinct topic—communications about unapproved uses of approved or cleared medical products.

The FDA held a Part 15 hearing in November 2016 to hear from a broad range of stakeholders regarding this topic. The agency has now reopened the comment period for the docket opened in connection with that public hearing for an additional 90 days (until April 10, 2017) to allow interested parties an opportunity to review the 2 draft guidances before submitting comments to any of the relevant dockets.

The FDA also added a document to the docket for the public hearing titled, “Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products.”

This document provides additional background on the issues the FDA is considering as part of its review of the agency’s rules and policies relating to firm communications regarding unapproved uses of approved or cleared medical products, including a discussion of First Amendment considerations.

The FDA is requesting input on the memorandum as it relates to the questions set forth in the initial notice of public hearing.

Vials of drugs
Photo by Bill Branson

The US Food and Drug Administration (FDA) has released 3 new draft guidance documents for industry.

One document provides an overview of scientific considerations when attempting to demonstrate that a biosimilar product is interchangeable with a reference product.

The other 2 guidance documents are intended to clarify the FDA’s position regarding communications about medical products.

The first draft guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” is intended to assist applicants in demonstrating that a proposed therapeutic protein product (eg, monoclonal antibodies) is interchangeable with a reference product under section 351(k) of the Public Health Service Act.

An interchangeable biological product is biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient. 

For a biological product that is administered more than once, the risk in terms of safety or diminished efficacy of alternating or switching between the biological product and the reference product must not be greater than the risk of using the reference product without such alternating/switching.

The approval pathway for biosimilar and interchangeable products was established by the Biologics Price Competition and Innovation Act of 2009, which was enacted as part of the Affordable Care Act in March 2010.

The FDA’s draft guidance on biosimilars contains information on:

• Factors impacting the type and amount of data and information needed to support a demonstration of interchangeability
• The data and information needed to support a demonstration of interchangeability
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
• Recommendations regarding the use of US-licensed reference products in a switching study or studies
• Considerations for developing presentations (eg, container closure systems) for proposed interchangeable products.

In addition to soliciting comments on this draft guidance, the FDA is inviting comments on questions posed in the notice of availability about interchangeability in general, the regulation of interchangeable products over their life cycle, and questions about considerations regarding post-approval manufacturing changes. 

The FDA also released a Center for Drug Evaluation and Research “From Our Perspective,” by Leah Christl, describing aspects of this draft guidance.

For more information on how to submit comments on the draft guidance and questions posed in the notice of availability, see the Federal Register notice.

Medical communications

The FDA also released 2 draft guidance documents that, the agency says, will each help provide clarity for medical product companies, as well as other interested parties, on the FDA’s current thinking and recommendations for a few different types of communications about medical products.

The first draft guidance, “Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities,” explains the FDA’s current thinking and recommendations on firms’ communication of healthcare economic information about approved drugs under section 502(a) of the Federal Food, Drug, and Cosmetic Act, which was recently amended by the 21st Century Cures Act. 

The guidance also answers common questions and provides the FDA’s recommendations regarding firms’ communications to payors about investigational drugs and devices that are not yet approved or cleared for any use.

The second draft guidance, “Medical Product Communications That Are Consistent With the FDA-Required Labeling,” explains the FDA’s current thinking about firms’ medical product communications that include data and information that are not contained in their products’ FDA-required labeling, but that concern the approved or cleared uses of their products.

The FDA has opened a public comment period for each draft guidance.

The agency is also asking for stakeholder input on another, distinct topic—communications about unapproved uses of approved or cleared medical products.

The FDA held a Part 15 hearing in November 2016 to hear from a broad range of stakeholders regarding this topic. The agency has now reopened the comment period for the docket opened in connection with that public hearing for an additional 90 days (until April 10, 2017) to allow interested parties an opportunity to review the 2 draft guidances before submitting comments to any of the relevant dockets.

The FDA also added a document to the docket for the public hearing titled, “Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products.”

This document provides additional background on the issues the FDA is considering as part of its review of the agency’s rules and policies relating to firm communications regarding unapproved uses of approved or cleared medical products, including a discussion of First Amendment considerations.

The FDA is requesting input on the memorandum as it relates to the questions set forth in the initial notice of public hearing.

Vials of drugs
Photo by Bill Branson

The US Food and Drug Administration (FDA) has released 3 new draft guidance documents for industry.

One document provides an overview of scientific considerations when attempting to demonstrate that a biosimilar product is interchangeable with a reference product.

The other 2 guidance documents are intended to clarify the FDA’s position regarding communications about medical products.

The first draft guidance, “Considerations in Demonstrating Interchangeability With a Reference Product,” is intended to assist applicants in demonstrating that a proposed therapeutic protein product (eg, monoclonal antibodies) is interchangeable with a reference product under section 351(k) of the Public Health Service Act.

An interchangeable biological product is biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient. 

For a biological product that is administered more than once, the risk in terms of safety or diminished efficacy of alternating or switching between the biological product and the reference product must not be greater than the risk of using the reference product without such alternating/switching.

The approval pathway for biosimilar and interchangeable products was established by the Biologics Price Competition and Innovation Act of 2009, which was enacted as part of the Affordable Care Act in March 2010.

The FDA’s draft guidance on biosimilars contains information on:

• Factors impacting the type and amount of data and information needed to support a demonstration of interchangeability
• The data and information needed to support a demonstration of interchangeability
• Considerations for the design and analysis of a switching study or studies to support a demonstration of interchangeability
• Recommendations regarding the use of US-licensed reference products in a switching study or studies
• Considerations for developing presentations (eg, container closure systems) for proposed interchangeable products.

In addition to soliciting comments on this draft guidance, the FDA is inviting comments on questions posed in the notice of availability about interchangeability in general, the regulation of interchangeable products over their life cycle, and questions about considerations regarding post-approval manufacturing changes. 

The FDA also released a Center for Drug Evaluation and Research “From Our Perspective,” by Leah Christl, describing aspects of this draft guidance.

For more information on how to submit comments on the draft guidance and questions posed in the notice of availability, see the Federal Register notice.

Medical communications

The FDA also released 2 draft guidance documents that, the agency says, will each help provide clarity for medical product companies, as well as other interested parties, on the FDA’s current thinking and recommendations for a few different types of communications about medical products.

The first draft guidance, “Drug and Device Manufacturer Communications with Payors, Formulary Committees, and Similar Entities,” explains the FDA’s current thinking and recommendations on firms’ communication of healthcare economic information about approved drugs under section 502(a) of the Federal Food, Drug, and Cosmetic Act, which was recently amended by the 21st Century Cures Act. 

The guidance also answers common questions and provides the FDA’s recommendations regarding firms’ communications to payors about investigational drugs and devices that are not yet approved or cleared for any use.

The second draft guidance, “Medical Product Communications That Are Consistent With the FDA-Required Labeling,” explains the FDA’s current thinking about firms’ medical product communications that include data and information that are not contained in their products’ FDA-required labeling, but that concern the approved or cleared uses of their products.

The FDA has opened a public comment period for each draft guidance.

The agency is also asking for stakeholder input on another, distinct topic—communications about unapproved uses of approved or cleared medical products.

The FDA held a Part 15 hearing in November 2016 to hear from a broad range of stakeholders regarding this topic. The agency has now reopened the comment period for the docket opened in connection with that public hearing for an additional 90 days (until April 10, 2017) to allow interested parties an opportunity to review the 2 draft guidances before submitting comments to any of the relevant dockets.

The FDA also added a document to the docket for the public hearing titled, “Memorandum: Public Health Interests and First Amendment Considerations Related to Manufacturer Communications Regarding Unapproved Uses of Approved or Cleared Medical Products.”

This document provides additional background on the issues the FDA is considering as part of its review of the agency’s rules and policies relating to firm communications regarding unapproved uses of approved or cleared medical products, including a discussion of First Amendment considerations.

The FDA is requesting input on the memorandum as it relates to the questions set forth in the initial notice of public hearing.

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

Cancer patient receiving
chemotherapy
Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has issued a complete response letter (CRL) regarding the new drug application (NDA) for an intravenous (IV) formulation of rolapitant.

An oral formulation of rolapitant, marketed as VARUBI®, is FDA-approved for use in combination with other antiemetic agents to prevent delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy in adults.

The NDA for rolapitant IV is for the same indication.

The FDA requested additional information regarding the in vitro method utilized to demonstrate comparability of drug product produced at the 2 proposed commercial manufacturers for rolapitant IV that were included in the NDA.

TESARO Inc., the company developing rolapitant IV, said it is working to provide the requested information.

The CRL did not identify concerns related to the safety or efficacy of rolapitant IV or request additional clinical studies. No concerns were raised regarding the active pharmaceutical ingredient, which is also used for VARUBI®.

TESARO identified potential deficiencies at the original contract manufacturer for rolapitant IV, secured a second drug product supplier, and included data from this manufacturer in the NDA.

During the NDA review, the FDA requested and TESARO provided in vitro data to demonstrate comparability of drug product made at the 2 manufacturing sites.

“TESARO is committed to bringing this new intravenous formulation of rolapitant to physicians and patients to enable additional flexibility and choice of antiemetic regimens, and we plan to address FDA’s questions expeditiously and complete this application, which we expect to enable approval in the first half of 2017,” said Mary Lynne Hedley, PhD, president and chief operating officer of TESARO.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

First month’s supply of
venetoclax (US version)
Photo courtesy of Abbvie

The Australian Therapeutic Goods Administration (TGA) has approved the BCL-2 inhibitor venetoclax (Venclexta™, formerly ABT-199) for use in certain patients with chronic lymphocytic leukemia (CLL).

The drug is now approved to treat Australian patients with relapsed or refractory CLL who have 17p deletion or no other treatment options.

Venetoclax is being developed by AbbVie and Genentech, a member of the Roche Group. The drug is jointly commercialized by the companies in the US and by AbbVie outside of the US.

Now that venetoclax has been approved by the TGA, it can be registered on the Australian Register of Therapeutic Goods and legally marketed and sold in Australia.

To make the drug affordable to the Australian public, the manufacturer can apply to the Pharmaceutical Benefits Advisory Committee to have the cost of the drug subsidized by the Australian government on the Pharmaceutical Benefits Scheme (PBS).

Venetoclax is not listed on the PBS. Historically, the delay between TGA approval and PBS listing ranges from 14 months to 31 months for cancer drugs.

Phase 2 trials

Venetoclax has produced high objective response rates (ORR) in two phase 2 trials of CLL patients.

In one of these trials, researchers tested venetoclax in 107 patients with previously treated CLL and 17p deletion. The results were published in The Lancet Oncology in June 2016.

The ORR in this trial was 79%. At the time of analysis, the median duration of response had not been reached. The same was true for progression-free survival and overall survival.

The progression-free survival estimate for 12 months was 72%, and the overall survival estimate was 87%.

The incidence of treatment-emergent adverse events was 96%, and the incidence of serious adverse events was 55%.

Grade 3 laboratory tumor lysis syndrome (TLS) was reported in 5 patients. Three of these patients continued on venetoclax, but 2 patients required a dose interruption of 1 day each.

In the second trial, researchers tested venetoclax in 64 patients with CLL who had failed treatment with ibrutinib and/or idelalisib. Results from this trial were presented at the 2016 ASH Annual Meeting.

The ORR was 67%. At 11.8 months of follow-up, the median duration of response, progression-free survival, and overall survival had not been reached. The estimated 12-month progression-free survival was 80%.

The incidence of adverse events was 100%, and the incidence of serious adverse events was 53%. No clinical TLS was observed, but 1 patient met Howard criteria for laboratory TLS.

In the past, TLS has caused deaths in patients receiving venetoclax. In response, AbbVie stopped dose-escalation in patients receiving the drug and suspended enrollment in phase 1 trials.

However, researchers subsequently found that a modified dosing schedule, prophylaxis, and patient monitoring can reduce the risk of TLS.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.

Micrograph showing CLL

The US Food and Drug Administration (FDA) has granted orphan drug designation for the combination of TG-1101 (ublituximab) and TGR-1202 for the treatment of patients with chronic lymphocytic leukemia (CLL).

Ublituximab is a glycoengineered anti-CD20 monoclonal antibody, and TGR-1202 is a next-generation PI3K delta inhibitor. Both drugs are being developed by TG Therapeutics, Inc.

Researchers have evaluated ublituximab and TGR-1202 in combination in a phase 1 trial of patients with relapsed or refractory CLL/small lymphocytic lymphoma (SLL) and non-Hodgkin lymphomas (NHLs).

Results were presented at the 2015 ASH Annual Meeting.

There was a 3+3 dose-escalation portion of the study and a dose-expansion phase. The patients received  TGR-1202 at doses ranging from 400 mg to 1200 mg and 2 different doses of ublituximab—900 mg for patients with NHL and 600 mg or 900 mg for patients with CLL/SLL.

As of ASH, there were 58 patients evaluable for efficacy and 71 evaluable for safety.

There were 10 CLL/SLL patients exposed to higher doses of TGR-1202. Among these patients, the overall response rate was 80%. Seven patients achieved a partial response, 1 achieved a complete response, and the remaining 2 patients had stable disease.

For the entire safety population, the most common adverse events were nausea (46%), diarrhea (44%), fatigue (41%), neutropenia (30%), and infusion-related reactions (25%).

Grade 3/4 adverse events included neutropenia (25%), diarrhea (3%), fatigue (3%), dyspnea (3%), pyrexia (3%), nausea (1%), infusion-related reactions (1%), sinusitis (1%), anemia (1%), hypophosphatemia (1%), and peripheral edema (1%). 

Now, the combination of ublituximab and TGR-1202 is being evaluated in the UNITY-CLL phase 3 trial for patients with previously treated or untreated CLL.

“[W]ith enrollment into our UNITY-CLL phase 3 trial currently exceeding our expectations, we expect to be able to commence a regulatory filing for the combination in 2018, and having orphan drug designation will provide certain cost-saving advantages for us during the regulatory approval process,” said Michael S. Weiss, executive chairman and chief executive officer of TG Therapeutics. 

The FDA grants orphan designation to drugs and biologics intended to treat, diagnose, or prevent diseases/disorders that affect fewer than 200,000 people in the US.

The designation provides incentives for sponsors to develop products for rare diseases. This may include tax credits toward the cost of clinical trials, prescription drug user fee waivers, and 7 years of market exclusivity if the product is approved.