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
Type |
Number Submitted |
Number Filed |
RTF, UN, WF |
First Action within Goal (%) |
Submissions Overdue (%) |
Establishment Applications |
5 |
5 |
0 |
100 % |
0 % |
New Product Applications |
16 |
16 |
0 |
100 % |
0 % |
Effectiveness Supplements |
15 |
15 |
0 |
100 % |
0 % |
Manufacturing Supplements |
339 |
338 |
1 |
98 % |
0 % |
Resubmissions |
8 |
n/a |
n/a |
100 % |
0 % |
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.
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:
Drug |
Species |
Type of Action |
Clenbuterol hydrochloride |
Horses |
New Chemical Entity |
Desoxycorticosterone pivalate |
Dogs |
New Chemical Entity |
Deslorelin acetate |
Horses (mares) |
New Chemical Entity |
Hemoglobin |
Dogs |
New Chemical Entity |
Colistimethate sodium |
Chickens (1-3 day) |
New Chemical Entity |
Doxycycline hyclate |
Dogs |
New Chemical Entity |
Difloxacin hydrochloride |
Dogs |
New Chemical Entity |
Competitive exclusion culture |
Chickens |
New Chemical Entity |
B-aminopropionitrile fumarate |
Horses |
New Chemical Entity |
Etodolac |
Dogs |
New Chemical Entity |
Enrofloxacin |
Cattle |
New Species |
Imidocarb dipropionate |
Dogs |
New Species |
Bacitracin methylene disalicylate |
Quail |
New Species |
Flunixin meglumine |
Cattle |
New Species |
Milbemycin oxime |
Cats |
New Species |
Formalin |
Finfish |
New Species |
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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