CDER 2004 Report to the Nation

CDER Report to the Nation: 2004

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1 Drug Review

Index

Highlights
New Drug and Biologic Review
Definitions
- Review statistics
- Notable 2004 new drug approvals
New or Expanded Use Review

Highlights

Many Americans benefited from last year’s timely reviews of new prescription medicines, over-the-counter medicines and the generic equivalents for both. When we review a medicine, we use the best science available to determine if a medicine’s benefits outweigh its risks for its intended use. An internal study showed that about half of our professional staff time is spent on safety assessment. We oversee the development of new medicines in the United States, and our paramount concern is the safety of patient volunteers in clinical trials.

Highlights for 2004 include:

n 119 new medicines. We approved 113 drugs and six biologics (29 priority and 90 standard reviews).

n 36 truly new medicines. We approved 31 drugs and five new biologics that had never been marketed before in any form in this country (21 priority and 15 standard reviews).

n 147 new treatment options. We approved new or expanded uses for 133 already approved drugs and 14 already approved biologics (48 priority and 99 standard reviews).

n 13 medicines for cancer. Our approvals included seven priority new medicines and six priority new or expanded uses for existing medicines.

n 8 over-the-counter drugs. Our approvals included five new medicines to be sold over the counter without a prescription, and four of them can be used by children. We approved three new uses for existing OTCs, all of which can be used by children.

n 15 “orphan” medicines. Our approvals included 11 new medicines and four new or expanded uses for patient populations of 200,000 or fewer.

n Medicines for children. We provided 23 priority reviews of pediatric studies of already approved medicines. These resulted in seven medicines gaining approval for new or expanded uses in children.

n 380 generic drugs. We gave final approval to 380 generic versions of existing drugs and tentative approval to another 95. We received 635 marketing applications for generic drugs.

n User fee goals. We exceeded all our performance goals for the fiscal year 2003 receipt cohort, the latest year for which we have full statistics. We are on track for exceeding all user-fee performance goals for the fiscal year 2004 cohort.

n 730 clinical trial inspections. We conducted foreign and domestic inspections that help protect volunteers in clinical trials from research risks and validate the quality and integrity of data submitted to us.

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New Drug and Biologic Review

Definitions

New drug applications. NDAs are the formal submissions of data that sponsors send us when they are seeking approval to market a “new drug” in the United States. Some NDAs are NMEs; however, “new drugs” can also include an active substance previously sold in a different form.

Biologic license applications. BLAs are the formal submissions of data that sponsors send us when they are seeking approval to market a biologic in the United States. A “new BLA” is a biologic that has never been approved for marketing in the United States.

New molecular entities. NMEs contain an active substance that has never before been approved for marketing in any form in the United States. Because of high interest in truly new medicines, we report approvals of NMEs and “new BLAs.” The charts for all NDAs and all BLAs include NMEs and new BLAs.

Review and approval times. Review time represents the time that we spend examining the application. Approval time represents our review time plus industry’s response time to our requests for additional information.

Priority approvals. These products represent significant improvements compared with marketed products. We have a goal of reviewing 90 percent of these applications within six months.

Standard approvals. These products have therapeutic qualities similar to those of already marketed products. We have a goal of reviewing 90 percent of these applications within 10 months.

Actions and filings. An application is “filed” when we determine it is complete and accept it for review. We make a filing decision within 60 days of receiving an application. Approval is one of the actions that we can take once an application is filed. Other actions include seeking more information from the sponsor. There is no direct connection between applications filed in one year and actions in the same year.

Orphan drugs. We administer a program that provides incentives to develop drugs for use in patient populations of 200,000 or fewer. Sponsors of orphan drugs receive inducements that include seven-year marketing exclusivity, tax credit for the product-associated clinical research, research design assistance from FDA and grants of up to $200,000 a year.

Accelerated approval. This program helps make products for serious or life-threatening diseases available earlier in the development process. We base our approval on a promising effect of the drug that can be observed significantly sooner than a long-term clinical benefit. Sponsors perform additional studies to demonstrate long-term clinical benefit.

Fast track development. This program facilitates the development and expedites our review of new drugs and biologics that demonstrate the potential to address unmet medical needs for serious or life-threatening conditions. Fast track emphasizes our close, early communication with sponsors.

2002 data. The higher review and approval times in 2002 resulted from the approval of some older applications and a decrease in applications filed.

Median times. Our charts show review and approval times as “medians.” The value for the median time is the number that falls in the middle of the group after the numbers are ranked in order. It provides a truer picture of our performance than average time, which can be unduly influenced by a few very long or short times. Our guide to understanding median approval time statistics is available at http://www.fda.gov/cder/present/MedianAPtime/index.htm.

Therapeutic BLAs included starting with 2004 data

Beginning with 2004, our charts incorporate data on the review of therapeutic biologics transferred to us in late 2003. These include:

n   Monoclonal antibodies.
n   Cytokines.
n   Growth factors.
n   Enzymes.
n   Other therapeutic immunotherapies.

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NDA and BLA Review Statistics

Approval totals

n   119 drugs and biologics
o 113 drugs
o 6 biologics

n   36 truly new medicines
o 31 NMEs
o 5 new BLAs

n   15 orphan approvals
o 11 NDAs (includes 9 NMEs)
o 4 new or expanded uses

Priority new drugs and biologics

n   29 total approvals
o 25 drugs
o 4 biologics

n   Median review time: 6.0 months
n   Median approval time: 6.0 months

n   31 filings
n   42 actions

n   9 orphan approvals (includes 8 NMEs)

Priority new molecular entities and new biologics

n   21 total approvals
o 17 NMEs
o 4 new BLAs

n   Median review time: 6.0 months
n   Median approval time: 6.0 months

n   17 filings

n   8 orphan approvals

Standard drugs and biologics

n   90 total approvals
o 88 drugs
o 2 biologics

n   Median review time: 11.9 months
n   Median approval time: 12.9 months

n   77 filings

n   162 actions

n   2 orphan approvals (including 1 NME)

Standard new molecular entities and new biologics

n 15 total approvals
o 14 NMEs
o 1 new BLA

n   Median review time: 16.0 months
n   Median approval time: 24.7 months

n   16 filings

n   1 orphan approval

Listing of NMEs, new BLAs, other priority NDAs

NMEs (P=priority, S=standard, O=orphan)

n   Acamprosate calcium (P)
n   Apomorphine hydrochloride (P, O)
n   Azacitidine (P, O)
n   Cinacalcet hydrochloride (P, O)
n   Clofarabine (P, O)
n   Darifenacin hydrobromide (S)
n   Duloxetine hydrochloride (S)
n   Erlotinib hydrochloride (P)
n   Eszopiclone (S)
n   Gadobenate dimeglumine (S)
n   Human secretin (P)
n   Hyaluronidase (P)
n   Iloprost (P, O)
n   Insulin glulisine (S)
n   Lanthanum carbonate (S)
n   L-Glutamine (S, O)
n   Omega-3-acid ethyl esters (S)
n   Ovine hyaluronidase (P)
n   Pegaptanib sodium (P)
n   Pemetrexed disodium (P, O)
n   Pentetate calcium trisodium (P, O)
n   Pentetate zinc trisodium (P, O)
n   Pregabalin (P)
n   Rifaximin (S)
n   Solifenacin succinate (S)
n   Telithromycin (S)
n   Tinidazole (S)
n   Tiotropium bromide (S)
n   Trospium chloride (S)
n   Trypan blue (P)
n   Ziconotide (P)

New BLAs

n   Bevacizumab (P)
n   Cetuximab (P)
n   Natalizumab (P)
n   Palifermin (P)
n   Technetium 99m Tc fanolesomab (S)

Other NDA priority approvals (T=tentative)

n   Acetylcysteine
n   Desloratadine
n   Emtricitabine; tenofovir disoproxil fumarate
n   Insoluble Prussian blue (T)
n   Nitazoxanide
n   Pentetate calcium trisodium (T)
n   Pentetate zinc trisodium (T)
n   Saquinavir mesylate

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Drugs@FDA

Drugs@FDA—the most frequently used application on the FDA Web site—has official information about FDA approved brand-name and generic drugs such as:

n   Approved and tentatively approved drug products.
n   The regulatory history of an approved drug.
n   Labels for approved drug products.
n   All drugs with a specific active ingredient.
n   Generic drug products for a brand-name drug product.
n   Therapeutically equivalent drug products for a brand-name or generic drug product.
n   Consumer information for drugs approved after 1998.

To use Drugs@FDA, go to our home page (http://www.fda.gov/cder) and click on “Drugs@FDA.”

Internet resources for drug review statistics

n Additional statistics. More review statistics are available at http://www.fda.gov/cder/rdmt/default.htm.

n Data updated. You should be aware that these data may differ from those in previous issues of this report. We have revised data from previous years.

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Notable 2004 New Approvals

Last year’s approvals benefited people with diabetes, neurological disorders, infections, cancer, heart disease and other disorders.

People with diabetes

Insulin glulisine (Apidra) is a rapid-acting, synthetic insulin that starts working faster than regular insulin but does not work as long. It is approved for adults and is used with a longer-acting insulin or by itself in an insulin pump to maintain proper blood sugar control. (NME)

People with depression

Duloxetine hydrochloride (Cymbalta) treats depression. It belongs to a class of medicines called serotonin and norepinephrine reuptake inhibitors. The label carries our warning (click here) about suicidal thoughts or actions in children, adolescents and adults. (NME)

People with neurological disorders

Apomorphine hydrochloride (Apokyn) treats loss of control of body movements in people with advanced Parkinson’s disease. (NME, priority, orphan)

Natalizumab (Tysabri), which received accelerated approval in November 2004, represented a new approach to treating patients with relapsing forms of multiple sclerosis. In February 2005, however, we issued a public health advisory to inform patients and health care providers about natalizumab’s suspended marketing while we and the manufacturer evaluate serious adverse events reported with its use. (biologic, priority)

People with pain

Ziconotide (Prialt) helps in the management of severe chronic pain in people who are intolerant of or refractory to other treatment. It is used with an implanted pump that injects the drug into the space around the spinal cord. (NME, priority)

Pregabalin (Lyrica) helps manage pain associated with diabetic peripheral neuropathy. (NME, priority)

People with cancer

Azacitidine (Vidaza) treats patients with myelodysplastic syndrome, a group of conditions caused by a problem in the blood-forming cells of bone marrow. (NME, priority, orphan)

Bevacizumab (Avastin) is used with intravenous 5-FU based chemotherapy as a first-line treatment for patients with cancer of the colon or rectum that has spread to other areas of the body. (biologic, priority)

Cetuximab (Erbitux) treats a type of cancer of the colon or rectum that has spread to other areas of the body and is known as EGFR-expressing metastatic colorectal carcinoma. It is the first monoclonal antibody approved to treat this type of cancer and is given intravenously in combination with irinotecan, another drug approved to fight colorectal cancer, or alone if patients cannot tolerate irinotecan. (biologic, priority)

Clofarabine (Clolar) treats 1- to 21-year-old patients with acute lymphoblastic leukemia that has relapsed after at least two treatments or is unresponsive to treatment. Also known as ALL, the disease is responsible for 80 percent of the acute leukemias of childhood. (NME, priority, orphan)

Erlotinib hydrochloride (Tarceva) treats non small-cell lung cancer that has spread within the lung or other parts of the body after failure of at least one prior chemotherapy regimen. (NME, priority)

Palifermin (Kepivance) is used to reduce the chances of developing mucositis, a severe injury to the cells lining the mouth, and to shorten the time with severe mucositis in patients with cancer who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. It is a modified version of a naturally occurring human growth factor that helps maintain the normal structure of the skin and gastrointestinal surface. (biologic, priority)

Pemetrexed (Alimta) in combination with cisplatin treats patients with malignant pleural mesothelioma. It is an orphan drug and the first approved for cancer of the mesothelium, a membrane that covers and protects most of the internal organs of the body. The disease is rare and usually associated with a history of asbestos exposure. (NME, priority, orphan)

People with alcoholism

Acamprosate calcium (Campral) helps patients with alcoholism stay alcohol-free after they have stopped drinking. (NME, priority)

Infectious diseases

Nitazoxanide (Alinia) treats diarrhea caused by parasites. For diarrhea caused by Giardia lamblia, an oral suspension can be used for patients 1 year of age and older and tablets can be used for patients older than 12. The oral suspension can also treat diarrhea caused by Cryptosporidium parvum in patients 1 to 11 years of age. (priority)

Rifaximin (Xifaxan) is a nonsystemic antibiotic used to treat traveler’s diarrhea caused by Escherichia coli. The drug does not enter the bloodstream. (NME)

Tinidazole (Tindamax) treats infections caused by parasites in both adults and pediatric patients older than 3 years of age. It treats trichomoniasis, a sexually transmitted disease, and the intestinal infections, giardiasis and amebiasis. (NME)

Telithromycin (Ketek) is an antibiotic to treat certain respiratory infections in adults 18 years of age and older. (NME)

People with lung disease

Tiotropium bromide (Spiriva HandiHaler) is for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease, including chronic bronchitis and emphysema. (NME)

People with pulmonary hypertension

Iloprost (Ventavis) treats pulmonary arterial hypertension, high blood pressure in the artery that carries oxygen-poor blood from the heart to the lungs. The inhaled drug helps dilate blood vessels in the lungs. (NME, priority, orphan)

People with macular degeneration

Pegaptanib sodium (Macugen) slows vision loss in people with the eye disease known as neovascular (wet) age-related macular degeneration. The drug is a selective vascular endothelial growth factor antagonist and is among the first treatments to target the underlying biology of this disease. (NME, priority)

People with end-stage kidney disease

Lanthanum carbonate (Fosrenol) is used to reduce the buildup of phosphates in patients with end-stage kidney disease. Fosrenol mixes with phosphates from food in the stomach to stop the phosphates from passing into the body. While small amounts of phosphates are needed by all cells in the body for them to work the right way, normal kidneys remove excess phosphate that can weaken bones. (NME)

People with HIV infection

Saquinavir mesylate (Invirase) and the combination of emtricitabine and tenofovir disoproxil fumarate (Truvada), in combination with other antiretroviral agents, treat adults with HIV. (both priority)

Children with allergies, hives

Desloratadine (Clarinex Syrup), a new pediatric formulation, treats allergy symptoms and hives in children from 6 months old to 2 years old. (priority)

Counterterrorism treatments

For NME and new drug tentative approvals click here.

People with other disorders

Acetylcysteine (Acetadote) prevents or lessens injury to the liver when administered within 8 to 10 hours after swallowing a potentially liver-damaging quantity of acetaminophen. (priority, orphan)

Cinacalcet hydrochloride (Sensipar) treats patients with high levels of parathyroid hormone in their blood due to chronic kidney disease that requires dialysis or with high levels of calcium in their blood due to cancer of the parathyroid gland. (NME, priority, orphan)

Darifenacin hydrobromide (Enablex), solifenacin succinate (VESIcare) and trospium chloride (Sanctura) treat an overactive bladder. (NMEs)

Eszopiclone (Lunesta) treats insomnia. (NME)

L-glutamine (NutreStore) treats short bowel syndrome in patients receiving specialized nutritional support when used with a recombinant human growth hormone approved for this indication. The manufacturer discontinued this product. (NME, orphan)

Omega-3-acid ethyl esters (Omacor) are used along with diet to lower very high triglyceride levels in adults. Elevated blood levels of triglycerides appear to increase the risk of developing heart disease. (NME)

Diagnostic and treatment aids

Gadobenate dimeglumine (Multihance) is a contrast agent used in magnetic resonance imaging of the central nervous system. (NME)

Human secretin (ChiRhoStim) can be used to stimulate the pancreas as an aid in the diagnosis of pancreatic disease. (NME, priority)

Hyaluronidase (Amphadase) and Ovine hyaluronidase (Vitrase) help to increase the absorption and dispersion of other injected drugs. (NME, priority)

Technetium 99m Tc fanolesomab (NeutroSpec) helps in the imaging of patients with equivocal signs and symptoms of appendicitis who are 5 years of age or older. It is a kit to prepare a radiolabled monoclonal antibody. (biologic)

Trypan blue (VisionBlue) helps in eye surgery by staining the part of the eye that holds the lens in place. (NME, priority)

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New or Expanded Use Review

Applications for a new or expanded use, often representing important new treatment options, are formally called “efficacy supplements” to the original new drug application.

We have a goal of reviewing standard supplements in 10 months and priority supplements in six months.

New or expanded use review statistics

Approval totals

n 147 drugs and biologics
o 133 drugs
o 14 biologics

Priority new or expanded uses (efficacy supplements)

n   48 total approvals
o 46 drugs
o 2 biologics

n   Median review time: 6.0 months
n   Median approval time: 6.0 months

n   64 actions

n   23 pediatric approvals (click here)

n   2 orphan approvals

25 priority approvals [number of approvals]
(Click here for 23 pediatric priority approvals)

n   Docetaxel [2]
n   Duloxetine [1]
n   Gatifloxacin [2]
n   Gemcitabine hydrochloride [1]
n   Icodextrin [1]
n   Interferon gamma-1b [1] (biologic)
n   Leflunomide [1]
n   Letrozole [1]
n   Levofloxacin [5]
n   Linezolid [3]
n   Moxifloxacin hydrochloride [2]
n   Multi-vitamin infusion without vitamin K [1]
n   Oxaliplatin [1]
n   Rofecoxib [2]
n   Tositumomab and iodine I 131 tositumomab [1] (biologic)

Standard new or expanded uses (efficacy supplements)

n   99 total approvals
o 87 drugs
o 12 biologics

n   Median review time: 10.0 months
n   Median approval time: 10.0 months

n   161 actions

n   2 orphan approvals

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Notable 2004 new or expanded use approvals

People with cancer

Docetaxel (Taxotere), in combination with the steroid prednisone, treats advanced metastatic prostate cancer. This is the first drug for hormone refractory prostate cancer that has shown a survival benefit. The drug’s uses were also expanded for use in combination with other chemotherapy for treatment of patients with operable node positive breast cancer. (priority)

Gemcitabine hydrochloride (Gemzar), in combination with the cancer chemotherapy paclitaxel, is a first-line treatment for patients with breast cancer that has spread and who have had a failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated. (priority)

Interferon gamma-1b (Actimmune), a treatment to reduce the frequency and severity of serious infections in people with chronic granulomatous disease, now has safety and efficacy data for pediatric patients. (biologic, priority)

Letrozole (Femara) can now be used with other chemotherapy for the extended treatment of early breast cancer in postmenopausal women who have received five years of tamoxifen therapy. (priority)

Oxaliplatin (Eloxatin), in combination with other chemotherapy, can now be used to treat patients previously untreated for advanced cancer of the colon and rectum. (priority)

Tositumomab and iodine I 131 tositumomab (Bexxar) can now treat patients with relapsed or refractory, low grade, follicular or transformed CD20 positive non-Hodgkin’s lymphoma who have not received rituximab. (biologic, priority)

People with diabetes

Duloxetine hydrochloride (Cymbalta), a treatment for depression (click here), can now be used for the management of neuropathic pain associated with diabetic peripheral neuropathy. It carries our warning (click here) about suicidal thoughts or actions in children, adolescents and adults. (priority)

People on artificial feeding

Multi-vitamin infusion without vitamin K (MVI-12) is used to prevent vitamin deficiency and complications from blood clots in people receiving home parenteral nutrition who also receive warfarin-type blood thinning therapy. (priority, orphan)

People on dialysis

Icodextrin (Extraneal Peritoneal Dialysis Solution), used for continuous ambulatory peritoneal dialysis or automated peritoneal dialysis for the management of chronic renal failure, is an improvement over normal solutions in certain patients. (priority)

Counterterrorism treatment

Click here for the expanded use of Penicillin G procaine to prevent the occurrence or progression of anthrax disease following exposure to Bacillus anthracis (including inhalational anthrax). (priority)

Pediatric new or expanded uses

Click here for the drugs with new or expanded uses in children approved under priority review required by the Best Pharmaceuticals for Children Act.

Antimicrobial Resistance

Drug-resistant bacteria continue to be a major threat to the public health.

In an effort to help protect public health, we provided priority reviews of new or expanded uses for four antibiotics to treat community acquired pneumonia due to multi-drug resistant Streptococcus pneumoniae. The antibiotics are Gatifloxacin (Tequin), Levofloxacin (Levaquin), Linezolid (Zyvox) and Moxifloxacin hydrochloride (Avelox). Linezolid was also approved to treat hospital-acquired pneumonia caused by Streptococcus pneumoniae, including multi-drug resistant strains.

Education campaign

We continued our antimicrobial resistance education campaign partnership with the Centers for Disease Control and Prevention and jointly released two new print public service announcements—one English and one Spanish. In addition to the print public service announcements, a Spanish-language brochure also was produced.

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Date created: Aug. 22, 2005