Biologics

STATUS OF PROGRAM

FY 1998 Accomplishments:

1. FDAMA Implementation

As the first anniversary of the Food and Drug Administration Modernization Act of 1997 (FDAMA) enactment passes, FDA has met nearly all of the deadlines for implementing the many varied provisions of the law. In many cases, FDA was able to complete these important initiatives well ahead of schedule.

FDAMA is a wide-ranging piece of legislation affecting the work of each the Agency's key components. The law explicitly required FDA to complete 17 regulations, 11 guidance documents, six regulatory notices, nine reports and at least 18 other tasks. In addition, scores of other regulatory measures were deemed necessary by the Agency to effectively meet the law's objectives.

Initiatives that have been completed during FDAMA's implementation include:

• A final rule, "Dissemination of Information on Unapproved/New Uses for Marketed Drugs, Biologics, and Devices", establishing parameters for distributing sound and balanced information about "off-label uses" for marketed drugs, biologics and medical devices. The new rule requires that the dissemination of off-label information by a sponsor be tied to a commitment to adequately research this use and submit it to the Agency for approval.
• A guidance on FDA's fast track programs, which is designed to facilitate the development and evaluation of new drugs and biologics, and designed to treat serious and life-threatening illnesses. The guidance provides product sponsors and researchers with vital information on how to maximize their product development efforts.
• An Agency plan for statutory compliance with FDAMA was developed through a series of "stakeholder" meetings conducted throughout the United States. During these meetings, Agency officials reached out to the general public and to those segments of society most directly affected by FDA work to solicit their views on how the Agency can best meet its public health mission. Representatives from consumer groups, industry, health professional organizations, academia and other groups participated in these forums, which provided the Agency with valuable insights that will be used in its future policy and budgetary considerations.

A proposed rule regarding requirements for radiophamraceuticals "Regulations for In Vivo Radiopharmaceuticals Used for Diagnosis and Monitoring" was published in the Federal Register on May 22, 1998. The final regulation is due to be published within 18 months after FDAMA enactment.

A new regulation concerning postmarketing studies reporting is required by FDAMA. The regulation requires the submission of annual postmarketing studies progress reports to FDA by sponsors who have entered into an agreement with the FDA to conduct such studies. A status report of postmarketing studies will be published in the Federal Register annually.

A notice of availability of the guidance document, "Fast Track Drug Development Programs -- Designation, Development and Application Review", on these policies and procedures was published in November 1998, within one year of Act enactment. The guidance informs sponsors of a new product intended for the treatment of a serious or life-threatening condition, and which demonstrates the potential to address unmet medical needs, that they may request the Agency to designate the application as fast track, and the Agency will respond to the request within 60 days. Once the fast track designation is granted, the sponsor may request to submit portions of an incomplete application for review. The guidance also contains provisions for expedited withdrawal of approval, under certain conditions. FDA must also develop and disseminate to physicians and others a description of the provisions applicable to fast track applications.

The FDAMA also amends Section 351 of the PHS Act to provide for the biologics license application (BLA) and biologics license which codifies the REGO initiative. The BLA proposed rule was published on July 31, 1998. The proposed rule "Biological Products Regulated Under Section 351 of the Public Health Services Act; Implementation of Biologics License; Elimination of Establishment License and Product License" eliminates all references to establishment and product licences and applications.

There are many other important aspects of the law which have been implemented or are well on their way toward being implemented. FDA is continuing its efforts to meet all of the FDAMA objectives as quickly as possible.

2. AIDS and the Nation's Blood Supply

As the AIDS epidemic continues its second decade, sources predict the global number of documented cases of AIDS will increase tenfold by the year 2000. FDA continues its efforts to combat AIDS through research and review of biological products intended for the diagnosis, prevention, and treatment of AIDS and AIDS-related diseases.

FDA continues its efforts to approve safe and effective blood and blood products before marketing. The Center for Biologics Evaluation and Research (CBER) received 28 AIDS Investigational New Drug Applications (INDs), and Investigational Device Exemptions (IDEs), during FY 1998. CBER received the first HIV vaccine IND in 1987. Since then the Office of Vaccines Research and Review (OVRR) has received and reviewed 81 HIV vaccine INDs, 10 of which were submitted during FY 1998. Many of these INDs are NIH-sponsored studies of investigational HIV vaccine products either manufactured by biotechnology or vaccine companies or developed by academic researchers. To date a total of 36 HIV-1 vaccine products have entered phase 1-2 studies. These products encompass a variety of vaccine designs including recombinant and synthetic HIV-subunit proteins (envelope, core and regulatory proteins); live viral and bacterial vectors inserted with recombinant HIV-1 gene sequences; recombinant HIV-1 nucleic acids also referred to as DNA vaccines; and inactivated HIV-1 (as a therapeutic vaccine in HIV-infected subjects only). Studies to test the use of novel adjuvants combined with some of these products are ongoing. Seventeen of these 36 products are being studied in HIV-uninfected subjects as strictly preventative HIV-1 vaccines. Eight of the 36 products are being evaluated in HIV-infected subjects as strictly therapeutic vaccines. The other 11 products are being tested for use as both preventative and therapeutic vaccines.

FDA's broad-based, multi-disciplinary research programs have played a significant role in the development of vaccines, therapeutic agents, and test kits for possible use in AIDS and AIDS-related conditions by defining parameters that must be met regardless of product or sponsor. FDA continues to enlarge the scope of its AIDS-related activities as new data on HIV, AIDS, and AIDS-related diseases accumulate and as clinical trials of new therapies, vaccines, and diagnostic tests expand. This research includes work on HIV infections and vaccine models for its prevention and studies of the immune response to HIV.

FDA has strengthened its internal management of blood issues. FDA's center and field staff have strengthened their ability to collaborate effectively on enforcement and compliance. In addition, FDA and the Centers for Disease Control and Prevention (CDC), working with the National Hemophilia Foundation, jointly carry out a surveillance program to detect HIV and hepatitis among patients receiving coagulation products.

In July 1997, FDA initiated a Blood Action Plan to increase the effectiveness of its scientific and regulatory actions, and to ensure greater coordination with our PHS partners. The Plan addresses highly focused areas of concern such as emergency operations, a plan for evaluating and managing emerging infections that may pose a threat to the blood supply, updating of regulations including the incorporation into regulations of those recommendations needed to protect the blood supply, reinvention of blood regulations with the goal of simplifying paperwork and the movement to a standards based approach, clarifying the responsibility of industry to be able to notify product end users in recall and lookback situations. DHHS accepted this plan in March 1998. The plan is being jointly implemented by FDA, CDC, the National Institutes of Health (NIH), and the Health Care Finance Administration (HCFA).

FDA has broadened the composition of its Blood Products Advisory Committee (BPAC) and has improved its use of the committee as an independent source of expertise. FDA has reconfigured the BPAC to include broader representation from consumer advocates, care givers, ethicists and those who frequently use blood and blood products. In addition, FDA now brings emerging blood safety issues to the BPAC sooner and more frequently.

FDA has strengthened the overlapping safeguards that protect patients from unsuitable blood and blood products. Blood donations are also now screened for seven different infectious agents. Gene amplification based screening of blood donations for HIV and hepatitis C is currently being developed under FDA oversight.

The Tissue Action Plan was initiated to develop the policies, regulations and guidance documents needed to implement the "Proposed Approach to the Regulation of Cellular and Tissue-Based Products", published by FDA in the Federal Register in February 1996.

On November 25, 1997, FDA approved interleukin eleven (IL-11), a new bioengineered product that can reduce the need for frequent platelet transfusions following high-dose chemotherapy. Patients who have required platelet transfusions after chemotherapy in the past may benefit most from this new product. IL-11 belongs to a family of human growth factors which stimulate the growth of cells. It is administered as a daily injection under the skin when chemotherapy is completed. The genetically engineered version will be marketed under the trade name Neumega by Genetics Institute, Inc., Cambridge, Massachusetts.

An approval letter was issued on January 17, 1998, to Organon Teknika Corporation for Vironostika human T-lymphotropic virus (HTLV) type I and type II Microelisa System, an in-vitro diagnostic test for the detection of antibodies to HTLV-I and HTLV-II in human serum and plasma. The Vironostika HTLV-I/II Microelisa System is a modification of their previously licensed Vironostika HTLV-I Microelisa System product to additionally detect antibodies to HTLV-II. The test incorporates viral lysates from both the HTLV-I and HTLV-II viruses as well as recombinantly produced HTLV-I p21 E Antigen, simultaneously approved under a separate license at Organon Teknika B.V., Netherlands. This test is the second blood screening test approved to detect antibodies to both HTLV-I/II.

FDA approved the first of a new class of commercially available blood-derived products called fibrin sealants that are applied topically to help control bleeding on May 1, 1998. Fibrin sealants can be used to stop oozing from small, sometimes inaccessible, blood vessels during surgery when conventional surgical techniques are not feasible. The product is effective for use in cardiopulmonary bypass and colostomy operations, and also in situations when a traumatic injury to the spleen has occurred.

The main active ingredient of fibrin sealant is fibrinogen, a protein from human blood that forms a clot when combined with thrombin -- another blood protein that facilitates blood clotting. The product works by forming a flexible material over the oozing blood vessel that can often control bleeding within five minutes. Although many surgeons have legally prepared their own fibrin sealants, these locally prepared products are not standardized or consistent, and the available sources of fibrinogen are not virally inactivated. This product is manufactured by Oesterreichisches Institut Fuer Haemoderivate G.M.B.H. in Vienna, Austria, and distributed by Baxter Healthcare Corporation, Glendale, California under the brand name TISSEAL.

On May 6, 1998, FDA approved a virally inactivated, processed blood product manufactured from pooled human plasma that can serve as an alternative to fresh frozen plasma. The manufacturing process for this new product includes a solvent detergent procedure that inactivates some blood-borne viruses such as the human immunodeficiency virus (HIV, the AIDS virus), hepatitis B (HBV) and hepatitis C (HCV). This procedure is similar to ones used to inactivate viruses in numerous more extensively processed plasma-derived products, including some clotting factors used to treat hemophiliacs.

The new product, often referred to as SD plasma, is administered intravenously. Like fresh frozen plasma, it is approved for a limited number of conditions such as the treatment of various clotting disorders, a rare condition known as TTP, and bleeding related to the use of the drug warfarin (a so-called blood thinner). Donors of pooled plasma used to manufacture SD plasma, like all blood donors, are screened to help exclude those who are infected with any of several blood-borne disease agents, including HIV, HBV, and HCV. However, current testing methods, while extremely effective, do not always detect early infections.

Both SD plasma and fresh frozen plasma are manufactured with overlapping safeguards that result in effective, safe products. However, they have different safety profiles. On one hand, SD plasma is manufactured with a viral inactivation step that effectively eliminates viruses with a lipid envelope such as HIV, HBV, and HCV viruses, that may have been undetected through donor screening. On the other hand, fresh frozen plasma is obtained from single donors, rather than pooled from a few thousand donors. Viruses without lipid envelopes are not inactivated by SD treatment. Because fresh frozen plasma is not pooled, there may be less risk from these viruses, as well as from unknown agents, than with a pooled product. The new product is manufactured by V.I. Technologies, Inc., Melville, New York, with the trade name VIPLAS/SD. The company has a contract with the American Red Cross to distribute it.

The Immucor ABS2000, a blood screening device, and associated reagents were cleared and approved on June 30, 1998. Clearance for ABS2000 is significant because it is the first fully automated "walk-away" device cleared for use in the blood bank/transfusion service. The instrument uses solid phase agglutination technology to perform patient antibody screening, donor ABO/Rh confirmations, patient crossmatching, and patient ABO/Rh grouping. Antisera for use on the instrument includes Anti-A, Anti-B, two Anti-D reagents and Anti-CDE. These are all monoclonal antibodies previously approved by FDA. No modifications to the antisera were necessary to accommodate the additional intended use. Red cells for use on the instrument include reverse grouping cells and antibody detection cells. These are previously approved products requiring no change.

On October 23, 1998, Baxter Healthcare Corporation received FDA approval to manufacture Recombinate Antihemophilic Factor (recombinant) at its new biotechnology facility in Thousand Oaks, California. The FDA approval enabled Baxter to increase by up to 40 percent its global supply of recombinant Factor VIII, which is genetically engineered blood-clotting therapy for people with hemophilia A.

Since 1995, demand for recombinant Factor VIII has nearly doubled globally. While there have been increases in manufacturing capacity, they have not kept pace with the rapid growth in market demand for recombinant products. The increase in demand is due to numerous factors, including increased use to prevent bleeding rather than simply treating patients when bleeding occurs.

FDA has significantly increased its oversight of the blood industry. The Agency now inspects all blood facilities at least every two years, and problem facilities are inspected more often. FDA has repeatedly provided the blood industry with detailed and specific guidance about how to ensure that blood and blood products are as safe as possible. FDA routinely holds workshops for the blood industry, the academic community and health care providers.

3. Biotechnology and Therapeutics

Biotechnology continues to play an important role in the discovery and development of new biological products for the diagnosis, treatment, or prevention of serious and life-threatening diseases. Biotechnology techniques are now used routinely to produce novel and highly complex biological, therapeutic and diagnostic agents and vaccines. Biotechnology methods have led to the development of products that were previously not feasible; that may be less toxic because they are more specific (e.g., "programmed" to attack only tumor cells leaving healthy cells alone); and that can be economically manufactured in large quantities. Many of these products are intended for use against diseases for which no known therapy exists.

The considerable strides in technical development and scientific understanding regarding biological therapies in the last decade, have led to an impressive record of acceleration in development of safe and effective new biologic products. Areas of development have spanned: r-DNA-derived agents of cell and gene therapy; xenotransplantation; and combination device/biologics. The rich experience documented to date in the diagnosis, prophylaxis and therapy of metabolic and cardiovascular disorders, immune deficiencies, malignancies, anemia, growth disorders, transplantation, and autoimmune disease, has nurtured substantial enthusiasm for further exploration. This, in turn, has led to increasing numbers of regulatory submissions to FDA.

The rapidly evolving technologies have elicited a wide range of concerns regarding: production modes (culture conditions/transgenics/plants/insects); sources and controls for autologous/allogenic/xenogeneic cells/tissues configuration of combinations; models and quality controls for assessing performance of gene therapy vectors; clinical trial designs (surrogates, extrapolation, controls, types, etc.) for assessing efficacy. FDA has addressed such concerns through its research, consultation with internal and external scientific expertise, and development of appropriate policy and guidance for industry.

FDA received 355 investigational applications (INDs/IDEs/MFs) submissions in FY 1998. Biotechnology-produced products have increased dramatically from fewer than five INDs in FY 1980, to 327 in FY 1998. Over 8,200 investigational amendments were received during FY 1998 for therapeutic products. An important subset of this growth has been in the area of somatic cell and gene therapy which has grown from eight therapy protocols in FY 1991, to 124 somatic cell and gene therapy INDs in FY 1998. Importantly, adjunct procedures used in gene therapy such as stem cell isolation are also rapidly increasing, leading to a secondary rise in device and biological submissions related to this area. In an effort to facilitate the evaluation of proposed gene therapy protocols, the Agency and NIH have implemented several initiatives designed to enable the development of gene therapy protocols.

Many xenotransplantation policy initiatives have continued to be generated in this exciting and controversial new area of potential product development. A clinical hold letter was sent to all sponsors of INDs which used pig cells or tissues following two reports in the literature (Patience, Nature Medicine 3:282-286, 1997 and Le Tissier, Nature 389:681-682, 1997) which showed that it was possible in-vitro to infect human cell lines with porcine endogenous retroviruses. The letter stated that sponsors must develop and use assays of acceptable sensitivity and specificity to look for this virus before continuing to treat patients under their INDs. A workshop was held in January 1998, titled "Developing US Public Health Policy in Xenotransplantation". An HHS guidance entitled "Issues Posed by Use of Non Human Primate Xenografts in Humans" will be published for comment in the fall in the Federal Register which outlines Agency concerns about the use of this animal source at this time. Many other documents are also in the works including a Guidance to Industry on Xenotransplantation, a proposed rule on Xenotransplantation, and a proposed rule on public discussion of gene therapy and xenotherapy clinical trials, all of which are hoped to be published in early 1999. There are also plans for a Biologic Specimen Archive and a National Xeno Registry, for which the pilot project under contract was begun in October 1997.

FDA approved the first biotechnology product to treat patients with one type of non-Hodgkin's lymphoma (NHL), a cancer of the immune system, on November 26, 1997. The product, rituximab, is a monoclonal antibody that is effective for patients with low-grade B-cell NHL who have not responded to standard treatments. A monoclonal antibody is a version of the body's own disease fighters, created with the tools of genetic engineering. Rituximab targets and destroys white blood cells (B-cells) involved in the disease, resulting in significant tumor shrinkage with less severe side-effects than most cancer treatments.

In the United States, approximately 240,000 people have B-cell NHL, and about 50 percent of this group are of the low-grade or follicular subgroup of NHL, which is ultimately incurable. Patients with this type of NHL may remain in remission for years but eventually have multiple recurrences of their symptoms or relapses that occur more frequently over the course of the disease.

Rituximab is a genetically engineered version of a mouse antibody that contains both human and mouse components. It can be produced in large quantities in the laboratory. Because specific cells are targeted with rituximab, rather than all fast-growing cells, as is the case for most chemotherapy, NHL patients suffer fewer serious side effects than with other treatments.

On December 10, 1997, the FDA approved the licensing of the first monoclonal antibody to help prevent acute kidney transplant rejection. The product, daclizumab, was approved to be used in conjunction with a standard course of immunosuppressive therapy.

In 1996, about 11,100 people received kidney transplants. Approximately 40 percent of the time, signs of organ rejection appear, requiring additional intervention, including in a small percentage of these cases, the need for another transplant or kidney dialysis. Organ transplant patients must take immunosuppressive agents for the rest of their lives, and some of these agents have significant negative side-effects.

Daclizumab is a genetically engineered version of a mouse antibody that has been manufactured to have mostly human components to make it safer. Using the techniques of biotechnology, identical, cloned antibodies can be produced in large quantities in the laboratory. The product works by suppressing the action of specific immune cells, called T-cells, that have been activated by the body to attack the transplanted organ as foreign tissue. Other non-activated T-cells in the immune system are not affected by daclizumab. Because it targets specific cells in the immune system, it has minimal additional side-effects for patients who must still take immunosuppressive drugs.

Daclizumab is the first monoclonal antibody approved to help prevent signs of kidney rejection. It is the second monoclonal antibody approved to improve the success of organ transplants. Daclizumab will be marketed under the trade name Zenapax by Roche Laboratories, Inc., Nutley, New Jersey. FDA reviewed and approved the license application in six months.

FDA approved the first biotechnology product to treat deep diabetic foot and leg ulcers on December 16, 1998. This product, becaplermin, is produced through recombinant DNA technology, and when combined with standard care can improve the likelihood of complete healing.

About 16 million people in the United States have diabetes and approximately 15 percent develop chronic ulcers of the foot and leg. Patients with diabetic ulcers are at a higher risk for local and systemic infections and amputation.

A majority of diabetic ulcers are quite deep and also have an adequate blood supply. Becaplermin is approved to treat these ulcers, but is not currently indicated for other ulcers, such as those caused by pressure.

Becaplermin must be used as a topical treatment, along with the surgical removal of infected and dead tissue, daily cleaning, the strict avoidance of weigh-bearing activities and other standard measures for ulcer management.

The active ingredient in becaplermin is platelet derived growth factor (PDGF). This growth factor, normally found in the blood, is produced in the laboratory by inserting a gene into yeast. It works by recruiting and promoting cell growth that helps to heal the ulcer.

Becaplermin is manufactured by R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey. It will be marketed under the trade name Regranex Gel by Ortho-McNeil Pharmaceutical, Raritan, New Jersey.

The FDA approved a drug/biologic combination to treat chronic hepatitis C in patients who have relapsed following previous treatment with interferon alone on June 3, 1998. The two therapies that comprise this combination are Intron A (interferon alfa-2B recombinant for injection) and Rebetol (ribavirin) capsules. The following can be used to answer questions:

Hepatitis C is a blood-borne liver disease. It is estimated that 4 million people in the United States have chronic hepatitis C infection. In its chronic state, hepatitis C can lead to cirrhosis, liver cancer and liver failure. Chronic hepatitis C is the most common reason for liver transplantation in the United States today.

The combination of Intron A/Rebetol is not a cure for chronic hepatitis C, and it is unknown if this treatment will delay liver disease progression. It also is unknown how the two agents work together against the hepatitis C virus.

The combination appears to suppress blood levels of the hepatitis C virus better than retreating patients with interferon alone. The clinical trials showed that after six months of therapy followed by six months of follow-up without therapy, approximately 45 percent of patients treated with the combination were able to sustain reduced hepatitis C virus levels compared to 5 percent who were retreated with interferon alone. Although 34 percent of patients treated with interferon alone had improvement in inflammation on an end-of-study liver biopsy, more patients (50 percent) treated with the combination improved.

Serious side effects have occurred with treatment and patients should be closely monitored by their physicians. Both Rebetol and Intron A have been found to cause significant adverse reproductive effects, including fetal death or structural malformations, in the developing fetus in several animal species. Therefore, women must not become pregnant while receiving this therapy and for six months after completing therapy.

Rebetol causes anemia, which can be serious especially in patients with underlying cardiovascular disease. Intron A has been associated with psychiatric disorders, including depression and suicidal behavior (suicidal thoughts, suicide attempts and completed suicides). Depression, suicidal ideation and suicides occurred in patients treated with the combination of Intron A/Rebetol. Lastly, most patients who receive Intron A therapy complain of "flu-like" symptoms, fevers, chills and body aches that are often relieved with nonprescription medicines such as acetaminophen or ibuprofen. Schering Corporation of Kenilworth, N.J., will market the combination as Rebetron and include detailed patient information with each dispensed package.

On June 19, 1998, FDA approved a monoclonal antibody to protect high-risk infants against the worst effects of respiratory syncytial virus (RSV) disease, the most common cause of lower respiratory infections in children. The product, palivizumab, is a genetically engineered antibody against the RSV virus. This antibody is manufactured using human and mouse antibody genes and can be produced consistently on a large scale.

Palivizumab is the second product licensed for RSV disease. The first, RSV Immune Globulin Intravenous (Human) (RSVIGIV) is made from human plasma and marketed as RespiGam by MedImmune Inc, Gaithersburg, Md, the same company marketing palivizumab. Both palivizumab and RSVIGIV are approved for use in high risk infants under two years old with lung problems related to chronic bronchopulmonary dysplasia (BPD) or prematurity. Both products were found effective in reducing the number of hospitalizations due to RSV.

Although both products must be given in five monthly doses, the new product, palivizumab, is given intramuscularly, rather than by intravenous infusion over a period of hours. In addition, palivizumab is more concentrated than RSVIGIV, an advantage since infants with certain pulmonary diseases may retain excess fluids.

In the United States, estimates are that more than 90,000 children are hospitalized and 4,500 die each year from RSV disease. The RSV outbreaks occur in the U.S. during the late fall, winter and early spring. The first dose of either product is given in November before the start of the RSV season. Medimmune Inc., the manufacturer of palivizumab, has formed a marketing alliance with the Ross Products Division of Abbott Laboratories to sell the new market under the brand-name Synagis.

On August 24, 1998, FDA licensed a new biotechnology product to treat patients with moderate to severe Crohn's disease, a chronic, incurable inflammatory bowel disease that causes diarrhea, cramping and abdominal pain and in some cases open holes (fistulae) leading from the intestine to the skin. This product, a monoclonal antibody called infliximab, is the first approved treatment for Crohn's disease. It is a genetically engineered antibody against a protein, tumor necrosis factor alpha, that promotes inflammation in the body. It is manufactured using cells containing human and mouse antibody genes.

Infliximab is indicated for the reduction of the symptoms of moderate to severe Crohn's disease in patients who have not responded well to traditional treatments, including corticosteroids and other immunosuppressants and antibiotics. The improvement in patients who had taken infliximab was measured in terms of the number of liquid or soft stools, number and severity of abdominal cramps, and the overall sense of well-being. In a clinical trial, patients benefited most from the treatment within a two to four-week period following a single dose of infliximab. The percentage of patients who maintain benefits decreased over the next few months. Currently, data are limited and inconclusive on the product's long-term effectiveness.

In another clinical trial, the treatment reduced the number of draining fistulas that occur in some cases of Crohn's disease -- a benefit that lasted five months at most. There are no data on the retreatment of these fistulas. Because short-term use of infliximab has benefited patients with a serious disease, the product has received accelerated approval. As part of that approval, the manufacturer has committed to studies in the near future to help answer questions about the long-term safety and efficacy of infliximab. Infliximab is manufactured by Centocor, Inc. of Malvern Pa., and will be marketed under the trade-name Remicade.

On September 25, 1998, FDA licensed a new biologic approach for the treatment of metastatic breast cancer, or cancer that has spread beyond the breast and lymph nodes under the arm. The new intravenous product, trastuzumab (trade-name Herceptin), is approved for use alone for certain patients who have tried chemotherapy with little success or as a first-line treatment for metastatic disease when used in combination with paclitaxel (trade-name Taxol).

Herceptin is a monoclonal antibody bioengineered from part of a mouse antibody which is altered to closely resemble a human antibody. It binds to a protein called HER2 which is found on the surface of some normal cells and plays a role in regulating cell growth. In laboratory experiments, Herceptin inhibited tumor cell growth by this binding action. In the case of metastatic breast cancer cells, approximately 30 percent of tumors produce excess amounts of HER2. Only patients who have tumors with this characteristic have been studied and shown to benefit from the new, targeted approach using Herceptin.

Approximately 1.6 million women have been diagnosed with breast cancer in the United States with 180,000 new cases diagnosed each year, according to the American Cancer Society. When breast cancer tumors produce excess amounts of the HER2 protein, it appears that the cancer may be more aggressive.

The benefits of Herceptin were shown in two clinical trials. In a randomized, controlled clinical trial, 469 patients with metastatic disease who over-expressed HER2 were assigned to receive chemotherapy alone or chemotherapy in combination with Herceptin. As a group, the women who received chemotherapy plus Herceptin had less rapid tumor growth, more tumors were reduced 50 percent or more in size, and one-year survival rates were higher.

Specifically, the median time to disease progression was 7.2 months for those receiving Herceptin and chemotherapy and 4.5 months for patients receiving chemotherapy alone. The overall tumor response was 44 percent in the Herceptin group and 29 percent in the chemotherapy alone group. The one-year survival rate for the Herceptin combination treatment was 79 percent versus 68 percent for chemotherapy alone.

In a second clinical trial with 222 patients, Herceptin was found effective when used alone for a group of breast cancer patients who had relapsed following previous chemotherapy for metastatic disease. The tumor response rate was 14 percent overall, with 3 percent of patients having their tumors completely disappear. Tumor responses lasted in a range of 6 weeks to 18 months, with a median of 9 months. In both clinical trials, the patients who responded best to Herceptin had the highest levels of HER2 protein.

Testing of tumors from women with metastatic breast cancer is critical for the identification of the 25 to 30 percent of patients who over express HER2 and who can potentially benefit from treatment with Herceptin. A new test to measure HER2 protein in tumors and help identify patients who may benefit from Herceptin treatment was approved by the FDA's Center for Devices and Radiological Health (CDRH). The new test is called the DAKO HercepTest, manufactured by Dako, a Denmark-based company. Herceptin is administered as an intravenous infusion given weekly, and can be administered in an outpatient setting.

Herceptin is the second monoclonal antibody approved to treat cancer. The first, Rituxan (trade-name), was approved in November 1997, for patients with one type of non-Hodgkin's lymphoma, a cancer of the immune system. Herceptin is manufactured by Genentech, Inc., San Francisco, Calif. FDA's Center for Biologics Evaluation and Review (CBER) granted fast track and priority review status to Genentech's application for Herceptin, and reviewed and approved it in approximately 4.5 months.

4. Vaccines

FDA has the responsibility for ensuring that vaccines and related products (such as botulinum toxin, skin test reagents for tuberculosis, and allergenic products) are safe and effective and adequately labeled. Currently, vaccines against 25 diseases are licensed in the United States (although more than one vaccine against a particular disease may be licensed, for example the inactivated and live vaccines against polio). Vaccines against ten diseases (Hepatitis B, polio, Haemophilus influenzae type b, mumps, measles, rubella, diphtheria, tetanus, pertussis, and chicken pox) are recommended for all U.S. children, and vaccines against influenza and pneumococcal infections are recommended for all adults more than 65 years of age. Periodic tetanus and diphtheria booster vaccinations are recommended for all adults. The use of influenza vaccine among adults has, in recent years, increased markedly (to a current use of about 80 million doses/year). Additional vaccines are recommended for special groups (for example, Hepatitis A) or for travelers to particular areas (e.g., Salmonella typhi or Japanese encephalitis virus vaccines). Many additional vaccines are in various stages of investigation (e.g., HIV or Herpes simplex virus vaccines) and their Investigational New Drug applications (INDs) are being reviewed; licensure is being sought for other vaccines (e.g., rotaviral and Lyme disease vaccines) and their Product License Applications (PLAs) are under review.

The standardization and testing of vaccines for lot release is one of FDA's responsibilities, and this activity continues to be a major effort. Each year FDA is responsible for the development of the reassortant influenza viruses that are used by the manufacturers for vaccine production; FDA is also responsible for the development of the sera that is used for the assignment of potency and, with the manufacturers, potency testing for each lot. FDA tests many additional vaccines for potency and safety in its laboratories.

Section 314 of the National Childhood Injury Act of 1986, entitled "Review of Warnings, Use Instructions, and Precautionary Information", requires the Secretary of Health and Human Services to determine, by rule, whether the warnings, use instructions, and precautionary information issued by manufacturers of childhood vaccines listed in the Vaccine Injury Table (Section 2114 of the Public Health Service Act) adequately warn health care providers of the nature and extent of potential dangers posed by such vaccines. The FDA was delegated the authority by the Assistant Secretary for Health and Human Services to complete this task. FDA has completed its review of labeling as mandated and, again as mandated, has written a draft proposed rule that will require the manufacturers of all vaccines listed in Section 2114 of the PHS Act to adequately warn health care providers.

Vaccine safety remains a priority concern at FDA and several issues dominated laboratory activity on vaccine safety this year. The first issue stems from the finding of reverse transcriptase (RT) activity by PCR-based methods in several vaccines. Studies were carried out to validate the various PCR-based RT assays, eliminate false positive and negative results, and apply the assays to various vaccines. Simultaneously, other studies (based on cell cultivation) were carried out that showed that infectious, replication competent retroviruses were not present. Both of these studies were published by CBER scientists in Clinical and Diagnostic Virology. The second major issue dealt with assessing the consequences of the Simian Virus 40 (SV40) that was present in early polio vaccine (1950?s and early 60?s); a number of researchers have, in the past several years, reported finding SV40 in association with several specific tumors. FDA co-sponsored a large, international workshop on this subject during 1997, and has since been involved (along with the NIH and the CDC) in follow-up studies to: (1) validate the PCR-based assays for detecting SV40 in tissue; (2) establish the extent to which SV40 may be present in the human population; and, (3) establish whether SV40 was present in the human population prior to the advent of the polio vaccines. (The Proceedings of that workshop were published this year in Developments in Biological Standardization.) PCR studies have shown that current polio vaccines are free of contaminating SV40. Additional laboratory studies involving vaccine safety (for both current and anticipated vaccines) are underway; a substantial effort is in progress to assess potential safety issues associated with the DNA vaccines, a promising vaccine technology, as are research efforts to assess adventitious agents in viral vaccines.

FDA scientists continue to play an active role in many national and international groups and organizations involved in setting vaccine policy and utilization, including: the Interagency Group of the National Vaccine Program Office; the National Vaccine Advisory Committee; the Advisory Commission on Childhood Vaccines; the Advisory Committee on Immunization Practices; the Committee on Infectious Diseases of the American Academy of Pediatrics; the World Health Organization; the Children's Vaccine Initiative; and national vaccines control agencies such as the National Institute of Biological Standardization and Control (in the United Kingdom). For vaccines-related issues, FDA continues to work closely with the National Institutes of Health (especially NIAID), and the CDC. The Office of Vaccines Research and Review continues to play an active role in committees related to AIDS, such as the NIH HIV Vaccine Selection Committee. FDA staff have played key roles in CISET, the PHS Interagency Working Group on Influenza Pandemic Preparedness, and the Adult Immunization Plan.

The Agency has continued its broad-based, multi-disciplinary research program in bacterial, viral, and parasitic diseases. Its scientists continue to publish in quality peer-reviewed journals and to be invited to participate in national and international meetings. Among the many significant achievements not mentioned above are: the demonstration that CpG motifs within DNA fragments have an adjuvant-like effect (favoring a Th 1 immune profile) and help to protect naive animals from certain bacterial challenges, notably Francisella and Listeria organisms; continued investigations on the role of HIV-1 and HIV-2 accessory genes for viral replication, studies important for vaccine development and evaluation as well as for the development of potential drug therapies; continuation of studies involving the recently developed infectious Hepatitis C full-length, c-DNA clone, studies important for understanding Hepatitis C pathogenicity and immunity; study of maternally-derived measles antibody titer in HIV-infected infants and the infants response to measles vaccine, administered before 1 year of age; investigation of pathogenesis of developmental brain damage from neuroviruletn viruses; continued studies on TSE removal and disinfection; continued studies on the use of the MAPREC test (an in-vitro test) for the control (neurovirulence testing) of oral polio vaccine; continuing computer simulations of lipids, including lipid bilayers and model adjuvants; and, continuing studies of pertussis pathogenicity and mechanisms of immunity.

Since the start of FY 1998 five vaccine PLAs have been approved. The FDA licensed the first vaccine to help prevent rotaviral disease on August 31, 1998. Rotavirus infections are the most common cause of severe diarrhea and vomiting in infants in the United States.

In this country, approximately 80 percent of children develop symptoms of rotavirus infection before they are five years old, with the most severe cases occurring before the age of three. About 55,000 infants and children are hospitalized because of severe diarrhea and dehydration due to rotaviral disease, and about 20-40 of these children die each year. Worldwide, approximately 870,000 deaths annually are attributed to rotaviral disease, with the vast majority of these deaths in developing countries.

The vaccine is approved for the immunization of infants in a three dose schedule at ages 2, 4, and 6 months, when most other childhood vaccines are given. The vaccine is given orally. If a child is over six months old, it is not currently recommended that the vaccination schedule be started.

The vaccine was studied in nearly 7,000 infants, including approximately 2,000 who were given the vaccine in placebo-controlled trials both in the U.S. and abroad. In these controlled trials, the vaccine prevented at least half of all cases of rotavirus disease and at least 70 percent of the severe cases. Immunization with the rotavirus vaccine is not recommended for adults. Although adults get rotavirus infections as well, most adults do not become sick or have only mild illness. The rotavirus vaccine is manufactured by Wyeth Ayerst Laboratories, Marietta, PA, and will be marketed with the trade name "Rotashield".

Other significant approvals during FY 1998 included a new acellular pertussis vaccine (Certiva; North American Vaccine, Inc., approved on July 29, 1998), and a rabies vaccine (RabAvert; Chiron Cehring, GmbH & Co., approved on October 20, 1997). A PLA supplement for the use of BCG for a papillary cancer of the bladder (Organon Tecknika; approved during August 1998) was also approved, as was a supplement for a Hepatitis B vaccine (Engerix-B; SmithKline Beecham Biologicals approved on July 7, 1998) for use in Hepatitis C positive adults for prevention of Hepatitis B infection. PLA supplements for a number of standardized grass allergenic extracts were approved, and currently all the U.S. licensed allergenic grass extracts are standardized.

5. Postmarket Surveillance

Team Biologics is a partnership between the FDA's Office of Regulatory Affairs (ORA) and CBER. In October 1998, responsibility for conducting biennial inspections of biotech therapeutic product manufacturers was transferred from CBER to the Team Biologics/Core Team. The Core Team will include certified ORA investigators, CBER certified inspectors and specially trained compliance officers representing both ORA and CBER. FDA will develop a cadre of CBER product specialists whose training includes technical areas as well as a comprehensive understanding of ORA's inspectional approach. An essential key to the success of Team Biologics is joint training of core team members and product specialists. Several FDA staff participated in the training, both as planners and participants. Team Biologics training for Therapeutic and Biotechnology Derived Therapeutic Products and for Allergenic Products was held for ORA Core Team members and CBER Product Specialists from July 27 - 31 and August 3 - 6, 1998. CBER product specialists spoke on a variety of topics associated with the manufacture of therapeutic and biotechnology derived therapeutic products, including: cloning/rDNA, characterization of cell lines, cell bank storage, primary cell culture, fermentation/ascites production, harvest/recovery, purification, testing for adventious agents, virus inactivation/removal, and QC tests and methods.

In January 1998, Alpha Therapeutic Corp., a major manufacturer of products derived from human blood plasma, agreed to bring its manufacturing standards into compliance with federal regulations under a consent decree which FDA and the Department of Justice filed in the United States District Court in Los Angeles. The agreement follows several FDA inspections of the firm that documented extensive violations.

FDA investigators inspected the Los Angeles-based firm twice -- in April and in June - July 1996 -- and each time observed numerous deficiencies. The firm responded by submitting corrective action plans to remedy the deficiencies. However, a third inspection, conducted in February - June 1997, again documented numerous violations, many of which involved a failure to ensure that critical production processes, equipment and systems performed reliably and with the required precision. FDA inspectors also found deviations in the areas of employee training, computer security, record keeping, facilities, and investigations of product failure.

Under the terms of the consent decree, Alpha Therapeutic agreed to hire an outside consultant to assist the firm in ensuring that all production processes, facilities and controls are brought up to and remain in compliance with the public health laws and regulations.

Among other provisions, the firm agreed to strengthen its quality assurance and control program; to assess its management controls and organizational structure to ensure compliance with FDA requirements; to improve its internal audit system; and to improve its system of production and process controls. Alpha Therapeutic also agreed to improve its records management, including procedures for tracking returned products, and its reworking and reprocessing procedures.

The corrective actions, which will not adversely affect the availability of the firm's drugs and biological products, will be completed within specified timeframes and under the supervision of FDA and the court. The consent decree is part of FDA's continuing surveillance to ensure the safety of products derived from human blood plasma.

6. Prescription Drug User Fee Act

The Prescription Drug User Fee Act (PDUFA) authorized revenues from fees paid by the pharmaceutical industry to expedite review by the FDA of human drug applications. These revenues were directed by the Act toward accomplishment of goals identified in letters from the Commissioner of Food and Drugs to the Chairman of the Energy and Commerce Committee of the House of Representatives, and the Chairman of the Labor and Human Resources Committee of the Senate.

The FY 1998 goals were:

• Review and act on 90 percent of standard original NDAs and PLAs/BLAs filed during fiscal year 1998 within 12 months of receipt.
• Review and act on 90 percent of priority original NDA and PLA/BLA submissions filed during fiscal year 1998 within 6 months of receipt.
• Review and act on 90 percent of standard efficacy supplements filed during fiscal year 1998 within 12 months of receipt.
• Review and act on 90 percent of priority efficacy supplements filed during fiscal year 1998 within 6 months of receipt.
• Review and act on 90 percent of manufacturing supplements filed during fiscal year 1998 within 6 months of receipt.
• Review and act on 90 percent of all resubmitted original applications filed during fiscal year 1998 within 6 months of receipt, and review and act on 30 percent of Class I resubmitted original applications within 2 months of receipt.

Review Performance. The Prescription Drug User Fee Act established performance goals for the evaluation of applications for marketing drug and certain biological products. Review performance monitoring is being done in terms of cohorts, e.g., the FY 1998 cohort includes applications received from October 1, 1997 through September 30, 1998. Accomplishment of the FY 1998 performance goals is not immediately measurable at the close of the fiscal year. The measurable outcome will occur either 6 or 12 months after the last submission received in FY 1998, depending upon the category of submission. Performance goals of the Act began with FY 1994. CBER has met or exceeded its performance goals in fiscal years 1994 and 1997.

The table below shows CBER's performance on the PDUFA FY 1997 cohort. The data provided are as of September 30, 1998.

FY 1997 Cohort

RTF=Refuse to File
UN=Unacceptable for filing (User Fee not paid)
WF=Withdrawn before filing

The FY 1997 first action performance goal is to review and issue a comprehensive action letter within goal on at least 90 percent of the new product applications, effectiveness supplements, manufacturing supplements and resubmissions submitted and filed during FY 1997. This means that not more than 10 percent of new product applications, effectiveness supplements, manufacturing supplements and resubmissions received and filed during FY 1997 should be overdue. Overdue is defined for standard new product and standard effectiveness supplements as having not issued a comprehensive action letter within 12 months of receipt and filing of the application. Overdue is defined for priority new product , priority product supplements, manufacturing supplements and resubmissions as having not issued a comprehensive action letter within 6 months of receipt and filing of the application. The statute allows three additional months for review of original NDA, PLA, or ELA submissions that involve major amendments within the last three months of their usual review intervals.

7. Bioterrorism

FDA is currently involved in a number of bioterrorism activities. These activities include emergency support functions and the expeditious development and licensure of new drugs and vaccines to prevent and treat conditions caused by exposure to biological warfare agents. FDA, under Emergency Support Function (ESF) #8, is the lead DHHS agency for assuring the safety of foods, drugs, medical devices, and biological products. As the lead DHHS agency under ESF, FDA is responsible for arranging the seizure, removal, and or destruction of contaminated and unsafe products in the event of a terrorist attack. Accordingly, FDA must be able to provide an appropriate second response to a potential biohazard event with adequately trained and equipped investigators.

Regarding the expeditious development and licensure of new vaccines and drugs, FDA is currently working with DOD and CDC on several bioterrorism fronts:

• Stockpiling of smallpox vaccine and vaccine immune globulin
• Consulting with manufacturers to outline steps to ensure the development of safe and effective vaccines. Numerous manufacturing problems pose barriers to the development of new vaccines
• Working with manufacturers of potential bioterrorist virus vaccines to develop clinical trial protocols to insure the safety and effectiveness of the vaccines. This is particularly complex with potential bioterrorist virus vaccines since clinical trials cannot be conducted on humans
• Reviewing the applications for drugs and biological agents that DOD is currently sponsoring

Efforts are being directed toward improving the safety and immunogenicity of anthrax vaccines to meet the threat of the use of anthrax spores as biowarfare agents. FDA scientists, in collaboration with a NIH scientist, authored, "Protection Against Anthrax Toxin by Vaccination with a DNA Plasmid Encoding Anthrax Protective Antigen." The article was published in Vaccine. Anthrax can cause lethal gastrointestinal and respiratory disease.

Animal Drugs and Feeds

STATUS OF PROGRAM

FY 1998 Accomplishments:

1. Review of New Product Applications

The Office of New Animal Drug Evaluation acted on 6,513 submissions for new animal drug applications (NADAs), abbreviated new animal drug applications (ANADAs), investigational new animal drug files (INADs) and generic investigational new animal drug (JINADs) files. Approximately 85 percent of these decisions were made within the statutory limit of 180 days for NADAs and ANADAs and the internally established time frame for INADs and JINADs. Of the 6,513 applications, 102 were for original applications (and reactivated originals) and 835 were for supplements to previously approved applications. In addition, 428 phased data submissions were completed by the Center during FY 1998. The on-time rate for these applications and substantial submissions was 75 percent.

Of the actions taken in FY 1998, FDA published 101 documents reflecting NADA and ANADA approvals in the Federal Register. These approvals included some very significant new product approvals, i.e., 10 new chemical entities, 10 products for use in new animal species, and four products available in new dosage forms. In addition, other approvals included 28 original generic approvals, four drug effectiveness study implementation (DESI) finalizations, five new product indications, and three additional production classes approved through supplements to existing approved drugs. A sampling is provided:

2. Animal Drug Availability Act (ADAA)

When the ADAA became law, the primary effect was to modify the effectiveness standard. The ADAA requires FDA to publish regulations to further define "adequate and well-controlled" studies and "substantial evidence." FDA is also required to announce proposals for legislative or regulatory change to the approval process for animal drugs intended for use in minor species or for minor uses as defined in section 512 of the Federal Food Drug and Cosmetic Act.

Since enactment of the ADAA, the Center for Veterinary Medicine published a final rule further defining "adequate and well-controlled studies." A proposed rule further defining "substantial evidence" was also published and the final rule on "substantial evidence" is currently being cleared by the agency for publication in the Federal Register. The rule was proposed to give FDA greater flexibility in determining the effectiveness of a new animal drug, thereby increasing the availability of approved animal drugs.

FDA has also completed and made available its proposals for legislative and regulatory change to facilitate the approval of animal drugs for use in minor species and for minor uses. A Notice of Availability of the report, "Proposals to Increase the Legal Availability of Animal Drugs for Minor Species and Minor Uses" was published in the October 29, 1998, Federal Register. A copy of the report is available upon request to FDA and is posted on CVM's Internet home page at http//www.fda.gov/cvm.

3. Bovine Spongiform Encephalopathy (BSE)

In March 1996, the British government announced its concern that exposure to BSE-infected beef might cause human disease. This concern grew because of a possible link between BSE (often called "mad cow" disease) and 22 cases of a newly identified variant of Creutzfeldt-Jakob Disease in humans. The potential impact on animal and human health and the high public health cost of a BSE epidemic in the U.S. has made the enforcement of the BSE rule a high priority for the Agency.

In FY 1998, CVM developed a cooperative effort with State regulators and other branches of FDA to implement the rule prohibiting feeding of certain mammalian tissue to cattle and other ruminants. The rule, which became effective on August 4, 1997, was designed to prevent the establishment and spread of BSE if it were to occur in U.S. cattle and reduce the potential risk to humans of new-variant Creutzfeldt-Jakob Disease. CVM's goal is to achieve 100 percent compliance with this regulation. A major objective in achieving this goal is to inspect all renderers, feed manufacturers, and a percentage of ruminant feeders within two years. Although considerable progress has been made toward this objective, FDA, in conjunction with its state counterparts, may take three years to accomplish this objective.

In addition to our inspection objective, CVM is actively pursuing educational initiatives. In FY 1998, CVM produced a satellite teleconference to foster educational and enforcement efforts concerning the rules on feeding animal protein to cattle. CVM partnered with the major groups representing the feed industry and regulators to produce the teleconference. The teleconference was broadcast across the country and became a major element of CVM's efforts to educate feed manufacturers about the rule. The broadcast was aired in 24 states, including all the major agricultural states, and was "downlinked" to approximately 240 sites.

4. National Antimicrobial Resistance Monitoring System (NARMS)

Important augmentations of the National Antimicrobial Resistance Monitoring System (NARMS) were made possible by funding from the President's National Food Safety Initiative during FY 1998. The augmentations include expanding the scope of the monitoring system and conducting follow-up research and investigations. NARMS, established in January 1996, is a collaborative effort among the FDA, USDA, and CDC which was initiated in response to public health issues associated with the approval of fluoroquinolone products for use in poultry.

The most important expansion of NARMS was inclusion of additional bacterial isolates in the database. In FY 1998, the animal database was expanded to include Campylobacter and E. coli isolate testing and reporting data as well as Salmonella. Human Campylobacter and E. coli isolates have been included in the monitoring system beginning in 1997. In addition, new sites and sources of isolates have been added. In FY 1998 the veterinary system incorporated data from a large number of slaughter plant isolates that were added to the sampling plan. The purpose was to more accurately reflect the risk from resistant pathogens in the food supply. In an attempt to mirror the reporting of human clinical isolates through the state public health laboratories, the veterinary side of NARMS has incorporated isolate collection from three sentinel sites in New York, Washington, and California.

Additional funding provided by the Food Safety Initiative was used in 1998 to initiate epidemiological research. NARMS data provided the basis for the research. The purpose of the research was to characterize and reduce the incidence of food borne disease associated with emerging and drug-resistant pathogens. It included a field study, several farm-based efforts, and molecular genetic research. During 1998, FDA, in collaboration with USDA and the Vermont Department of Health, studied risk factors associated with an outbreak of Salmonella Typhimurium DT104 on a Vermont dairy farm. Information from this field study will be used to educate farmers on prevention of future outbreaks and spread of this multi-resistant organism among animals and to man.

NARMS data was also used in CVM's work with other agencies. In collaboration with USDA, on-farm poultry studies have been initiated in five states in order to obtain information about management, production, and drug use practices that influence the development of resistant zoonotic pathogens. Collaborative molecular genetic studies have been funded with FDA's National Center for Toxicological Research to identify regions of fluoroquinolone resistance in zoonotic enteric organisms. This information will be used to develop genetic molecular detection capabilities. Later these techniques will be applied to zoonotic enterics and environmental bacteria to provide improved monitoring for resistance emergence and transfer. This work will significantly improve FDA's ability to monitor the safety of competitive exclusion products and new antimicrobial approvals.

5. Meat Residue Monitoring

The meat residue monitoring program is the foundation of the government's efforts to ensure that food derived from animals is safe for human consumption. The Residue Monitoring Program ensures that the products contain no harmful drug residues. FDA and USDA work closely with each other and state agencies in carrying out effective monitoring and efficient analytical methods to detect harmful residues.

In FY 1998, FDA concentrated on the development of draft policy options for implementing a residue program that incorporated the principles of a HACCP environment. FDA also worked with other Federal agencies to design a new USDA/FSIS National Residue Program based on slaughter plants assuming full responsibility for food safety under HACCP called the "National Cooperative Residue Program (NCRP)." The approach concentrates on the principle activities in controlling chemical and drug residues in meat, poultry, and eggs.

FDA continued to work with USDA to employ a balanced measure of education, voluntary compliance, and regulatory enforcement in programs designed to reduce drug residues. In FY 1998, FDA continued to participate as a member of the interagency Surveillance Advisory Team which designs the annual FSIS National Residue Plan. The team is now using decision tools and risk assessment to develop the plan. FDA also contributed to the educational effort by publishing information pertaining to residue profiles in various slaughter classes. Health implications of residues have also been published in major veterinary journals and reference books.

6. Electronic Submission of Information to CVM via the Internet

CVM successfully completed a pilot project to permit electronic submissions of Notices of Claimed Investigational Exemptions (NCIE). The pilot, which was developed in cooperation with the animal drug industry, is the only completely electronic submission system developed in FDA using the Internet and is the first step toward a paperless CVM. Under the pilot, CVM began accepting NCIE submissions electronically from participating sponsors on September 8, 1997.

The pilot evaluated the feasibility and efficiency of accepting regulatory required information sent to the Center via e-mail. CVM received 819 electronic submissions during the 13 month pilot. Processing time dropped from a median of 36 days for paper submissions to 8 days for electronic submissions. The pilot won strong support from the animal drug industry. CVM is taking steps to formalize the procedure as required by 21 CFR 11 (Electronic Signatures; Electronic Records).

CVM applied FDA's Final Rule on Electronic Records and Electronic Signatures (21 CFR Part 11) to the pilot. This rule, published on March 20, 1997, was designed to set the standards for Electronic Records for FDA and its regulated industries. CVM used this rule to accept electronic files as legal, original submissions for review in lieu of paper. After success of the NCIE pilot, CVM plans to expand the electronic submission program to include other regulatory reporting requirements, and is preparing a proposal to expand the approach to protocols and other more complex data submissions.

7. Dioxin Contamination

In July 1997, FDA found contamination of animal feeds with dioxin which resulted in elevated levels of dioxin in chickens and catfish. Dioxin is a potent carcinogen with potential additional toxic and reproductive properties. There are no tolerances or other administrative levels for dioxin in food or feed. Dioxin contamination was found in animal feeds distributed to over 3,400 consignees throughout the country.

After lengthy investigation, the source of the dioxin contamination was traced to a mined clay product called "ball clay," which is used as an anti-caking agent in soybean meal, in other feed components, and in complete animal feeds. CVM worked cooperatively with the affected industries to halt any further distribution and use of the feed known to be contaminated with dioxin. This was carried out across the country. FDA is taking steps to ensure that ball clay will not be used in food products in the future.

In FY 1998, FDA initiated steps to determine whether other mined clay products and naturally derived anticaking agents were contaminated with dioxin, similar to the findings in ball clay. Industry associations met with CVM to determine the type of information needed, which resulted in a compilation of industry sampling of anticaking agents for dioxins. FDA is working with EPA, as a supplement to industry sampling, to conduct a survey of mined feed anticaking agents for the presence of dioxins. In FY 1999 the results of this survey will be received and used in conjunction with the voluntary industry reports to determine if any additional actions are necessary.

8. Feed Mill Licensing

On October 9, 1996, the President signed the Animal Drug Availability Act of 1996 which, among other things, amends Section 512(m) of the Federal Food, Drug and Cosmetic Act to require a single facility license rather than multiple Medicated Feed Applications (MFA) for each feed mill as previously required. This amendment streamlines the paperwork process both CVM and the feed mill industry, for approval to manufacture of medicated feeds while maintaining current safeguards for the manufacture of medicated feed.

The previous process required each feed mill to have a license for the use of each medicated mix. As a result, many feed mills had multiple licenses. Under the new system, a feed mill needs only one license with FDA to use any of the restricted medicated articles. Feed mills were converted to the single license during 1998. To ensure no disruption to the industry the amendment allowed any feed manufacturing facility which held one or more approved MFAs to automatically have a transitional license. The transitional license period ended on April 8, 1998. FDA has approved 1,240 permanent license applications since the new process was implemented. Under the new process, feed manufacturers are still subject to the current good manufacturing practices (cGMPs) regulations and inspection by FDA or states under contract with the agency. All other existing reporting responsibilities for each drug remain unchanged. A proposed rule to amend the animal drug regulations and add a new part 515 to the Code of Federal Regulations to describe the requirements for feed mill licensing was published on July 30, 1997. The final rule has been developed and should be published soon.

9. Implementation of the Generic Animal Drug and Patent Term Restoration Act

Generic Animal Drugs undergo an Abbreviated New Animal Drug Application review process. In accordance with the Generic Animal Drug and Patent Term Restoration Act, FDA publishes a monthly listing of all approved new animal drug applications in the "FDA Approved New Animal Drug Products." This list includes information on drug approvals, sponsorship changes, application withdrawals, patent term expiration dates, exclusivity protection dates, and suitability petition dates.

FDA is working to publish new regulations to reflect the streamlined application review processes, and will include generic applications in this new regulatory matrix. Since 1992, 136 original generic applications have been approved, including 28 approvals in 1998.

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