FDA Perspective

Significant FDA Approvals in 1997

Am Fam Physician. 1998 Jun 1;57(11):2865-2868.

The U.S. Food and Drug Administration approved 132 new drugs and biologic products in 1997, the second highest number of approvals made in one year by the agency since initiation of the Prescription Drug User Fee Act of 1992.

Once again, the highlight of the year was a reduction in the median approval time for drugs and biologic products. The median approval time for 121 new drugs in 1997 was reduced by 6 percent to 14.4 months, compared with 15.4 months in 1996. Thirty-nine of these medications were new molecular entities (NMEs), products that had never been approved in any form in the United States. The median approval time for NMEs was 13.4 months, which was 6 percent faster than the 14.3-month approval time for NMEs in 1996. Since 1996, the FDA has reviewed and approved more than 90 NMEs.

New Molecular Entities

Four NMEs, including two antidiabetic agents, were approved in six months or less. Troglitazone (Rezulin) and repaglinide (Prandin) were approved for treatment of type 2 (non–insulin-dependent) diabetes. Nelfinavir (Viracept), a protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection, was approved in 2.6 months. A selective estrogen receptor modulator, raloxifene (Evista), was approved for prevention of osteoporosis in postmenopausal women.

Two of the five new cancer drugs approved last year were indicated for treatment of advanced breast cancer: toremifene (Fareston) and letrozole (Femara). The remaining three agents were approved for a variety of indications. Sterile aerosol talc (Sclerosol) was approved for the prevention of recurrence of malignant pleural effusion, samarium Sm-153 lexidronam (Quadramet) was approved for the treatment of pain associated with osteoblastic metastatic bone lesions, and dolasetron (Anzemet) was approved for the prevention of nausea and vomiting associated with chemotherapy and surgery.

The NME category also included fomepizole (Antizol), the first drug indicated as an antidote for ethylene glycol poisoning; clopidogrel (Plavix), for the reduction of atherosclerotic events; pramipexole (Mirapex) and ropinirole (Requip) for treatment of Parkinson's disease, and carbon-14-urea breath test (PYtest), a new diagnostic breath test for the detection of Helicobacter pylori.

In addition to 39 NMEs, 11 new product and biologic license applications (PLAs and BLAs) were approved in a median time of 14.5 months (20 percent faster than the 18.1 months' median time of the previous year). Ten of these major approvals were first-time approvals of products containing a substance or combination of substances never before approved for the U.S. market, compared with eight such approvals in the previous year. The agency's first-time approvals included seven therapeutic products and three vaccines. (One of the vaccines is a bulk product that is used only in the manufacture of Infanrix.) The 12 months' median time for first-time approvals in 1997 was 20 percent faster than the median time of 15.08 months required for such approvals in 1996.

Major biologic products approved last year included autologous cultured chondrocytes (Carticel), indicated for the repair of clinically significant, symptomatic cartilaginous defects caused by trauma; becaplermin (Regranex Gel 0.01 percent), for the treatment of diabetic neuropathic ulcers of the lower extremity, and interferon alfacon-1 (Infergan) for the treatment of chronic hepatitis C viral infection. The new biologic products are listed in Table 1.

TABLE 1

Significant New Biologic Products Approved in 1997

Product Use/indication

Therapeutics

Autologous cultured chondrocytes (Carticel)*

Repair of cartilaginous defects of the femoral condyle

Becaplermin (Regranex Gel 0.01%)*

Once-daily treatment of diabetic ulcers

Coagulation factor IX recombinant (BeneFIX)*†

Control and prevention of hemorrhagic episodes of hemophilia B

Daclizumab (Zenapax)*†

Prevention of acute renal allograft rejection

Interferon alfacon-1 (Infergan)*

Treatment of chronic hepatitis C

Oprelvekin (rhIL11; Neumega)*†

Prevention of severe thrombocytopenia following chemotherapy

Rituximab (Rituxan)*†

Treatment of relapsed or refractory low-grade or follicular, B-cell non-Hodgkin's lymphoma

Vaccine

Diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed vaccine (Infanrix)

Immunization of infants and children, 6 weeks to 7 years of age, against diphtheria, tetanus and pertussis

Rabies vaccine (RabAvert)

Immunization of children and adults against rabies


RhIL 11 = recombinant human interleukin 11.

* = U.S. approval was the first worldwide.

† = Orphan drug status.

TABLE 1   Significant New Biologic Products Approved in 1997

View Table

TABLE 1

Significant New Biologic Products Approved in 1997

Product Use/indication

Therapeutics

Autologous cultured chondrocytes (Carticel)*

Repair of cartilaginous defects of the femoral condyle

Becaplermin (Regranex Gel 0.01%)*

Once-daily treatment of diabetic ulcers

Coagulation factor IX recombinant (BeneFIX)*†

Control and prevention of hemorrhagic episodes of hemophilia B

Daclizumab (Zenapax)*†

Prevention of acute renal allograft rejection

Interferon alfacon-1 (Infergan)*

Treatment of chronic hepatitis C

Oprelvekin (rhIL11; Neumega)*†

Prevention of severe thrombocytopenia following chemotherapy

Rituximab (Rituxan)*†

Treatment of relapsed or refractory low-grade or follicular, B-cell non-Hodgkin's lymphoma

Vaccine

Diphtheria and tetanus toxoids and acellular pertussis (DTaP) adsorbed vaccine (Infanrix)

Immunization of infants and children, 6 weeks to 7 years of age, against diphtheria, tetanus and pertussis

Rabies vaccine (RabAvert)

Immunization of children and adults against rabies


RhIL 11 = recombinant human interleukin 11.

* = U.S. approval was the first worldwide.

† = Orphan drug status.

Also of note was the approval of software to enhance the safety of blood products, and new manufacturing and technologies to improve the safety of biologic products.

Major new indications approved for previously marketed biologic products included interferon alfa-2b (Intron A) for treatment of follicular lymphoma in conjunction with chemotherapy; abciximab (ReoPro) for treatment of unstable angina, and inactivated hepatitis A vaccine (Havrix) for prevention of hepatitis A in patients with chronic liver disease.

The new molecular entities are listed in Table 2. Five of these products have been designated as “orphan drugs”: anagrelide (Agrylin), fomepizole (Antizol), toremifene, calfactant (Infasurf intratracheal suspension) and sterile aerosol talc. Four biologic products, oprelvekin (Neumega), recombinant coagulation factor IX (BeneFIX), daclizumab (Zenapax) and rituximab (Rituxan), were also designated orphan drugs. Orphan designation is available for products used to treat conditions for which the incidence in the U.S. patient population would be less than 200,000 per year. The FDA usually provides assistance and special incentives to the manufacturers of orphan drugs.

TABLE 2

New Molecular Entity Drugs Approved in 1997

Drug Use/indication

Alatrofloxacin, intravenous (Trovan)*†

Once-daily treatment for bacterial infections

Anagrelide (Agrylin)‡§∥

First approved therapy for essential thrombocythemia

Arbutamine (GenESA Injection)*

Drug and intravenous delivery system to obtain stress heart rate in patients with coronary artery disease who cannot tolerate exercise

Ardeparin (Normiflo)*∥¶

Prevention of deep venous thrombosis

Bromfenac (Duract)*∥¶

Short-term management of pain

Calfactant (Infasurf Intratracheal Suspension)§

Prevention of and treatment for respiratory distress syndrome in premature infants

Carbon-14-urea breath test (PYtest)‡∥

Diagnostic breath test for detection of Helicobacter pylori

Cefdinir (Omnicef)*

Antibiotic for mild to moderate bacterial infections

Cerivastatin (Baycol)*†

Reducing elevated total and low-density lipoprotein cholesterol levels

Clopidogrel (Plavix)‡∥

Reducing atherosclerotic events in patients with documented atherosclerosis

Delavirdine (Rescriptor)‡∥#

Treatment of HIV-1 infection

Dolasetron (Anzemet)*

Prevention of chemotherapy- and postoperative-induced nausea and vomiting

Emedastine (Emadine)*∥

Temporary relief of the signs and symptoms of allergic conjunctivitis

Eprosartan (Teveten)*†

Hypertension

Fenoldopam (Corlopam)*∥

In-hospital, short-term (up to 48 hours) management of severe hypertension

Fomepizole (Antizol)*§∥

Antidote for ethylene glycol poisoning

Grepafloxacin (Raxar)*†

Bacterial infection

Imiquimod (Aldara Cream)*∥

External genital and perianal warts

Irbesartan (Avapro)*

Hypertension

Letrozole (Femara)*

Advanced breast cancer in postmenopausal women with disease progression after anti-estrogen therapy

Mangofodipir (Teslascan)*

Adjunct to MRI for detection, localization, characterization and evaluation of liver lesions

Mibefradil (Posicor)*¶

Hypertension and chronic stable angina pectoris

Nelfinavir (Viracept)‡∥#

HIV in adults and children

Pramipexole (Mirapex)*∥

Signs and symptoms of Parkinson's disease

Quetiapine (Seroquel)*†

Manifestations of psychotic disorders

Raloxifene (Evista)‡∥

Prevention of postmenopausal osteoporosis

Repaglinide (Prandin)‡∥

Lowers blood glucose in patients with type 2 diabetes mellitus

Ropinirole (Requip)*

Signs and symptoms of idiopathic Parkinson's disease

Samarium Sm-153 lexidronam (Quadramet) injection*∥

Relief of pain in patients with confirmed osteoblastic metastatic bone lesions

Sibutramine (Meridia)*∥

Management of obesity

Sterile aerosol talc (Sclerosol)‡§∥

Prevention of recurrence of malignant pleural effusions

Tamsulosin (Flomax)*

Signs and symptoms of benign prostatic hyperplasia

Tazarotene (Tazorac)*

Topical treatment of plaque psoriasis and mild to moderate facial acne vulgaris

Tiagabine (Gabitril)*

Adjunctive treatment for partial seizures in patients 12 years and older

Tiludronate (Skelid)*

Once-daily treatment for Paget's disease

Toremifene (Fareston)*§

Oral anti-estrogen for treatment of metastatic breast cancer in postmenopausal women with estrogen receptor–positive or receptor–unknown tumors

Troglitazone (Rezulin)†‡¶

Type 2 diabetes

Trovafloxacin (Trovan)*†

Once-daily oral treatment for bacterial infections

Zolmitriptan (Zomig)*

Acute migraine


HIV = human immunodeficiency virus; MRI = magnetic resonance imaging.

* = Standard classification.

† = U.S. approval was second worldwide.

‡ = Priority classification, representing an important therapeutic gain.

§ = Orphan drug status.

∥ = U.S. approval was first worldwide.

¶ = Significant postmarketing revisions in prescribing information.

# = Treatment of human immunodeficiency virus.

TABLE 2   New Molecular Entity Drugs Approved in 1997

View Table

TABLE 2

New Molecular Entity Drugs Approved in 1997

Drug Use/indication

Alatrofloxacin, intravenous (Trovan)*†

Once-daily treatment for bacterial infections

Anagrelide (Agrylin)‡§∥

First approved therapy for essential thrombocythemia

Arbutamine (GenESA Injection)*

Drug and intravenous delivery system to obtain stress heart rate in patients with coronary artery disease who cannot tolerate exercise

Ardeparin (Normiflo)*∥¶

Prevention of deep venous thrombosis

Bromfenac (Duract)*∥¶

Short-term management of pain

Calfactant (Infasurf Intratracheal Suspension)§

Prevention of and treatment for respiratory distress syndrome in premature infants

Carbon-14-urea breath test (PYtest)‡∥

Diagnostic breath test for detection of Helicobacter pylori

Cefdinir (Omnicef)*

Antibiotic for mild to moderate bacterial infections

Cerivastatin (Baycol)*†

Reducing elevated total and low-density lipoprotein cholesterol levels

Clopidogrel (Plavix)‡∥

Reducing atherosclerotic events in patients with documented atherosclerosis

Delavirdine (Rescriptor)‡∥#

Treatment of HIV-1 infection

Dolasetron (Anzemet)*

Prevention of chemotherapy- and postoperative-induced nausea and vomiting

Emedastine (Emadine)*∥

Temporary relief of the signs and symptoms of allergic conjunctivitis

Eprosartan (Teveten)*†

Hypertension

Fenoldopam (Corlopam)*∥

In-hospital, short-term (up to 48 hours) management of severe hypertension

Fomepizole (Antizol)*§∥

Antidote for ethylene glycol poisoning

Grepafloxacin (Raxar)*†

Bacterial infection

Imiquimod (Aldara Cream)*∥

External genital and perianal warts

Irbesartan (Avapro)*

Hypertension

Letrozole (Femara)*

Advanced breast cancer in postmenopausal women with disease progression after anti-estrogen therapy

Mangofodipir (Teslascan)*

Adjunct to MRI for detection, localization, characterization and evaluation of liver lesions

Mibefradil (Posicor)*¶

Hypertension and chronic stable angina pectoris

Nelfinavir (Viracept)‡∥#

HIV in adults and children

Pramipexole (Mirapex)*∥

Signs and symptoms of Parkinson's disease

Quetiapine (Seroquel)*†

Manifestations of psychotic disorders

Raloxifene (Evista)‡∥

Prevention of postmenopausal osteoporosis

Repaglinide (Prandin)‡∥

Lowers blood glucose in patients with type 2 diabetes mellitus

Ropinirole (Requip)*

Signs and symptoms of idiopathic Parkinson's disease

Samarium Sm-153 lexidronam (Quadramet) injection*∥

Relief of pain in patients with confirmed osteoblastic metastatic bone lesions

Sibutramine (Meridia)*∥

Management of obesity

Sterile aerosol talc (Sclerosol)‡§∥

Prevention of recurrence of malignant pleural effusions

Tamsulosin (Flomax)*

Signs and symptoms of benign prostatic hyperplasia

Tazarotene (Tazorac)*

Topical treatment of plaque psoriasis and mild to moderate facial acne vulgaris

Tiagabine (Gabitril)*

Adjunctive treatment for partial seizures in patients 12 years and older

Tiludronate (Skelid)*

Once-daily treatment for Paget's disease

Toremifene (Fareston)*§

Oral anti-estrogen for treatment of metastatic breast cancer in postmenopausal women with estrogen receptor–positive or receptor–unknown tumors

Troglitazone (Rezulin)†‡¶

Type 2 diabetes

Trovafloxacin (Trovan)*†

Once-daily oral treatment for bacterial infections

Zolmitriptan (Zomig)*

Acute migraine


HIV = human immunodeficiency virus; MRI = magnetic resonance imaging.

* = Standard classification.

† = U.S. approval was second worldwide.

‡ = Priority classification, representing an important therapeutic gain.

§ = Orphan drug status.

∥ = U.S. approval was first worldwide.

¶ = Significant postmarketing revisions in prescribing information.

# = Treatment of human immunodeficiency virus.

Anagrelide is the first medication approved in the United States for the treatment of essential thrombocythemia. The elevated blood platelet counts that occur in patients with thrombocythemia result in a high incidence of serious illnesses associated with blood clotting, including myocardial infarction and stroke. Anagrelide is indicated for the treatment of essential thrombocythemia to reduce the elevated platelet count and the risk of thrombosis, and to ameliorate associated symptoms.

Fomepizole, a synthetic alcohol dehydrogenase inhibitor, is the first drug approved as an antidote for ethylene glycol poisoning. Ingestion of ethylene glycol, which is a major component of antifreeze, may cause central nervous system depression (ataxia, slurred speech), metabolic acidosis, renal failure and death. According to the American Association of Poison Control Centers, 5,548 cases of ethylene glycol poisoning occurred in 1996.

Toremifene is indicated as a first-line treatment for metastatic breast cancer in post-menopausal women with estrogen receptor–positive or receptor–unknown tumors.

Calfactant, a natural lung surfactant, is indicated for the prevention of respiratory distress syndrome (RDS) in premature infants at high risk for RDS and for the treatment of premature infants who develop RDS.

Sclerosol intrapleural aerosol is a sterile talc in an aerosolized canister that can be used for the prevention of recurrence of malignant pleural effusions in symptomatic patients. Malignant pleural effusions may occur in a variety of disease states, including advanced cancer.

Biologic Products

Recombinant coagulation factor IX is the first recombinant clotting factor for the treatment of hemophilia B. Factor IX deficiency results in frequent hemorrhages in affected patients. Since the product is produced through recombinant DNA technology without the use of blood or plasma products, it is virtually free from the risk of transmission of human bloodborne pathogens such as HIV and hepatitis viruses. Recombinant coagulation factor IX is indicated for the control and prevention of hemorrhagic episodes in patients with hemophilia B, including control and prevention of bleeding in surgical settings.

Oprelvekin is the first platelet growth factor that promotes production of the body's platelet supply in patients with solid tumors or lymphoma who are undergoing chemotherapy for treatment of cancer. Oprelvekin is indicated for prevention of severe thrombocytopenia and reduction in the need for platelet transfusions following myelosuppressive chemotherapy.

Rituximab is the first monoclonal antibody approved for therapeutic use in patients with cancer. It is also the first new single-agent therapy developed in 10 years for treatment of non-Hodgkin's lymphoma. The agent is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell, non-Hodgkin's lymphoma.

Daclizumab is the first monoclonal antibody used for the prevention of acute rejection of a transplanted kidney. When added to therapy with other anti-rejection drugs, daclizumab reduced the incidence of kidney rejection episodes from 47 to 27 percent in one clinical trial and from 35 to 22 percent in a second trial.1 Daclizumab is indicated for prophylaxis of acute organ rejection in patients receiving renal transplants and is intended to be used as part of an immunosuppressive regimen that includes cyclosporine and corticosteroids.

New Safety Information

Pharmaceutical manufacturers significantly modified the prescribing information for four NMEs as a result of a number of safety issues identified by the FDA after the introduction of these agents to the market. Incidents of severe hepatitis and liver failure in patients taking bromfenac for more than one month resulted in revision of labeling to include a box warning regarding severe hepatic reactions, including jaundice, potentially fatal fulminant hepatitis and liver failure. Bromfenac is indicated only for the short-term (10 days or less) management of acute pain and is not indicated for long-term use.

In December of 1997, the FDA alerted health care providers to a serious safety issue associated with the use of low-molecular-weight heparins or heparinoids, including ardeparin. When these agents are used concurrently with spinal or epidural anesthesia or in cases of spinal puncture, bleeding or hematomas may occur within the spinal column. Permanent paralysis may result if the increased pressure on the spinal column is not treated immediately. The risk of bleeding or hematoma is increased if catheters are placed in the spinal canal or if other drugs that can affect blood clotting, such as nonsteroidal anti-inflammatory drugs, platelet inhibitors or other anticoagulants, are also used.

Approximately 35 postmarketing reports of liver injury, including liver failure, in patients taking troglitazone triggered a company-initiated change in the prescribing information that specified the need to monitor liver function in patients taking this drug. It is recommended that liver enzymes and bilirubin levels in patients taking troglitazone be measured at the start of therapy, monthly for the first six months of therapy, and every two months for the remainder of the first year of therapy.

The FDA advised health care providers about two warnings in the labeling of mibefradil. The first warning advised physicians against prescribing mibefradil to patients with an increased risk for developing low heart rates. This warning was developed after the FDA and the manufacturer received reports of dangerously lowered heart rates in about 20 patients. After the agency received seven reports of drug-associated muscle injury among patients who had taken mibefradil and simvastatin (Zocor), a new warning was added that advised health care providers against prescribing mibefradil for patients who are taking lovastatin (Mevacor) or simvastatin. Pending availability of further information, coadministration of mibefradil with any type of statin drug (i.e., any HMG–CoA reductase inhibitor) was strongly discouraged.

For further information on revised prescribing information for these and other agents, please visit the Medwatch Web page at www.fda.gov/medwatch.

Dr. Rheinstein, a family physician, is director of medicine staff at the U.S. Food and Drug Administration. Dr. Akbari is a postdoctoral fellow at Robert Wood Johnson Medical School, New Brunswick, New Jersey.

REFERENCE

1. Zenapax (daclizumab) package insert. Roche Pharmaceuticals, Hoffmann-La Roche Inc., 340 Kingsland St., Nutley, NJ 07110-1199.

Coordinator of this quarterly series from the U.S. Food and Drug Administration is Stuart L. Nightingale, M.D., Associate Commissioner for Health Affairs.


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