FDA advisory panel decisionsPerspective

FDA panel rejects continued marketing of calcitonin salmon for osteoporosis

The FDA’s Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee determined by a 12-9 vote that the benefit–risk assessment presented before them did not support calcitonin salmon nasal spray for the treatment of osteoporosis.

“Though the cancer signal raised by the clinical studies is inconclusive, it’s a consistent signal nonetheless. In addition, based on the available fracture data, there really has not been proven efficacy in that regard; particularly in the case of shortened periods of time — use of 1 to 2 years — which, to my understanding, is what’s being proposed by the sponsor,” Thomas Weber, MD, associate professor of medicine at Duke University Medical Center, and a temporary voting member with the Drug Safety and Risk Management Advisory Committee, said after a vote against support of the drug’s benefit–risk assessment. “For these reasons, and in light of the fact that I respect the decisions of past committees, we need to look at drugs critically using the best available science and evidence.”

According to the FDA briefing documents, products approved for this indication include calcitonin salmon (Miacalcin injection and nasal spray, Novartis Pharmaceuticals), calcitonin salmon recombinant (Fortical nasal spray, Upsher-Smith Laboratories) and generic equivalents.

Besides a risk–benefit assessment vote, the committee voted 20-1 in favor of requiring calcitonin salmon products currently in development to provide fracture efficacy data to gain approval for the indication of treatment or prevention of postmenopausal osteoporosis.

Richard Bockman, MD, PhD, head of endocrine service at the Hospital for Special Surgery in New York, held the lone vote against this measure.

“There are populations that benefit from the use of the medication. Why should we hold people who are going to bring the same product [salmon calcitonin] to a higher standard from what’s already approved?” Bockman said after his vote. “What you’ve just said is you’ve restricted the commercial field to the people who already own it at present and you’re blocking other companies from coming in and selling exactly the same product, theoretically for the same restrictions that we feel should be imposed upon this drug; and that it is not a general treatment for everybody with osteoporosis, but for very limited uses.”

Evidence of risk

Novartis conducted trial-level meta-analyses to evaluate the potential risk for malignancy in patients treated with all forms of calcitonin salmon following the prostate cancer signal noted in the osteoarthritis trials.

The results of all trials suggest higher risk for malignancies for patients treated with calcitonin compared with patients treated with placebo (OR=1.6; 95% CI, 1.1-2.3, and risk difference[RD]=1.6%; 95% CI, 0.5-2.8), according to data presented by the FDA.

Malignancy evaluations demonstrated meta-analysis results consistent with an increase in the incidence of malignancies with calcitonin salmon, with similar results across statistical methods and basal cell carcinoma being the most frequent malignancy.

After presentations from Novartis, David Moeny, RPh, MPH, USPHS, an epidemiologist from the FDA, said the manufacturer provided “poor documentation of methods utilized, failure to assess quality of included studies, and a high attrition and differential drop out.”

Higher overall risks for malignancies in calcitonin salmon vs. placebo were specified (nasal spray only: all malignancies RD=1.6%; 95% CI, 0.4-2.7 vs. non-basal cell carcinoma malignancies RD=0.9%; 95% CI, –0.2 to 1.9; and nasal spray plus oral: all malignancies RD=1%; 95% CI, 0.3-1.7 vs. non-basal cell carcinoma malignancies RD=0.5%; 95% CI, –0.1 to 1.2), according to data presented at the meeting. However, the FDA presenters stated that analyses of all malignancies were influenced by a single large trial of 5 years in duration.

“It’s difficult to adequately assess the strength of potential cancer signal with these data,” Janelle Charles, PhD, mathematical statistician from the office of biostatistics at the FDA, said during the meeting.

Worldwide concerns

Although calcitonin salmon has been marketed in the United States since 1975, few safety concerns have been raised in the postmarketing period. Recently, the potential risk for prostate cancer has been an issue of concern. The imbalance of prostate cancer data noted in two trials led to the joint meeting to decide whether marketing of the drug should continue.

In July, the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended that after taking into account the limited efficacy of calcitonin when used to treat postmenopausal osteoporosis to reduce the risk for vertebral fractures, the benefits of calcitonin-containing medicines did not outweigh their risks in this indication, according to FDA briefing documents.

Because the nasal spray is only used in osteoporosis, CHMP recommended that this formulation be withdrawn. According to the FDA briefing documents, CHMP has proposed that the injectable formulation should be used only for: prevention of acute bone loss due to sudden immobilization, with treatment recommended for 2 weeks with a maximum duration of 4 weeks; Paget’s disease in patients who do not respond to alternative treatments or for whom such treatments are not suitable, with treatment normally limited to 3 months; and patients with hypercalcemia caused by cancer. However, a formal decision by the European Commission regarding the adoption of CHMP’s recommendations is pending.

Furthermore, Health Canada informed Canadians in July that the agency is also assessing a potentially increased risk for cancer with long-term use of the drug, according to FDA documents. – by Samantha Costa

For more information:

Briefing Information for the March 5, 2013, Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee.

The FDA’s Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee determined by a 12-9 vote that the benefit–risk assessment presented before them did not support calcitonin salmon nasal spray for the treatment of osteoporosis.

“Though the cancer signal raised by the clinical studies is inconclusive, it’s a consistent signal nonetheless. In addition, based on the available fracture data, there really has not been proven efficacy in that regard; particularly in the case of shortened periods of time — use of 1 to 2 years — which, to my understanding, is what’s being proposed by the sponsor,” Thomas Weber, MD, associate professor of medicine at Duke University Medical Center, and a temporary voting member with the Drug Safety and Risk Management Advisory Committee, said after a vote against support of the drug’s benefit–risk assessment. “For these reasons, and in light of the fact that I respect the decisions of past committees, we need to look at drugs critically using the best available science and evidence.”

According to the FDA briefing documents, products approved for this indication include calcitonin salmon (Miacalcin injection and nasal spray, Novartis Pharmaceuticals), calcitonin salmon recombinant (Fortical nasal spray, Upsher-Smith Laboratories) and generic equivalents.

Besides a risk–benefit assessment vote, the committee voted 20-1 in favor of requiring calcitonin salmon products currently in development to provide fracture efficacy data to gain approval for the indication of treatment or prevention of postmenopausal osteoporosis.

Richard Bockman, MD, PhD, head of endocrine service at the Hospital for Special Surgery in New York, held the lone vote against this measure.

“There are populations that benefit from the use of the medication. Why should we hold people who are going to bring the same product [salmon calcitonin] to a higher standard from what’s already approved?” Bockman said after his vote. “What you’ve just said is you’ve restricted the commercial field to the people who already own it at present and you’re blocking other companies from coming in and selling exactly the same product, theoretically for the same restrictions that we feel should be imposed upon this drug; and that it is not a general treatment for everybody with osteoporosis, but for very limited uses.”

Evidence of risk

Novartis conducted trial-level meta-analyses to evaluate the potential risk for malignancy in patients treated with all forms of calcitonin salmon following the prostate cancer signal noted in the osteoarthritis trials.

The results of all trials suggest higher risk for malignancies for patients treated with calcitonin compared with patients treated with placebo (OR=1.6; 95% CI, 1.1-2.3, and risk difference[RD]=1.6%; 95% CI, 0.5-2.8), according to data presented by the FDA.

Malignancy evaluations demonstrated meta-analysis results consistent with an increase in the incidence of malignancies with calcitonin salmon, with similar results across statistical methods and basal cell carcinoma being the most frequent malignancy.

After presentations from Novartis, David Moeny, RPh, MPH, USPHS, an epidemiologist from the FDA, said the manufacturer provided “poor documentation of methods utilized, failure to assess quality of included studies, and a high attrition and differential drop out.”

Higher overall risks for malignancies in calcitonin salmon vs. placebo were specified (nasal spray only: all malignancies RD=1.6%; 95% CI, 0.4-2.7 vs. non-basal cell carcinoma malignancies RD=0.9%; 95% CI, –0.2 to 1.9; and nasal spray plus oral: all malignancies RD=1%; 95% CI, 0.3-1.7 vs. non-basal cell carcinoma malignancies RD=0.5%; 95% CI, –0.1 to 1.2), according to data presented at the meeting. However, the FDA presenters stated that analyses of all malignancies were influenced by a single large trial of 5 years in duration.

“It’s difficult to adequately assess the strength of potential cancer signal with these data,” Janelle Charles, PhD, mathematical statistician from the office of biostatistics at the FDA, said during the meeting.

Worldwide concerns

Although calcitonin salmon has been marketed in the United States since 1975, few safety concerns have been raised in the postmarketing period. Recently, the potential risk for prostate cancer has been an issue of concern. The imbalance of prostate cancer data noted in two trials led to the joint meeting to decide whether marketing of the drug should continue.

In July, the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP) recommended that after taking into account the limited efficacy of calcitonin when used to treat postmenopausal osteoporosis to reduce the risk for vertebral fractures, the benefits of calcitonin-containing medicines did not outweigh their risks in this indication, according to FDA briefing documents.

Because the nasal spray is only used in osteoporosis, CHMP recommended that this formulation be withdrawn. According to the FDA briefing documents, CHMP has proposed that the injectable formulation should be used only for: prevention of acute bone loss due to sudden immobilization, with treatment recommended for 2 weeks with a maximum duration of 4 weeks; Paget’s disease in patients who do not respond to alternative treatments or for whom such treatments are not suitable, with treatment normally limited to 3 months; and patients with hypercalcemia caused by cancer. However, a formal decision by the European Commission regarding the adoption of CHMP’s recommendations is pending.

Furthermore, Health Canada informed Canadians in July that the agency is also assessing a potentially increased risk for cancer with long-term use of the drug, according to FDA documents. – by Samantha Costa

For more information:

Briefing Information for the March 5, 2013, Joint Meeting of the Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee.

    Perspective
    Michael Kleerekoper

    Michael Kleerekoper

    Calcitonin is generally recognized as the least effective therapy for osteoporosis. Orthopedists recommend its use in the first 3 to 4 weeks after surgery, but few others still use it.

    Regarding the FDA requirement for anti-fracture efficacy — the FDA is holding osteoporosis drugs to a higher standard than many other preventive therapies. To my knowledge, lipid-lowering drugs and drugs for the treatment of hypertension or diabetes are not required by the FDA to prevent adverse outcomes. Rather, they are approved once they demonstrate a statistically significant difference in numbers (i.e. lower lipid levels, lower BP, lower HbA1c). They do not have to prove that they reduce heart disease or complications from diabetes.

    • Michael Kleerekoper, MD, MACE
    • Endocrine Today Editorial Board member Professor in the department of internal medicine Section chief in the endocrinology division University of Toledo School of Medicine Toledo, Ohio

    Disclosures: Kleerekoper reports no relevant financial disclosures.