CDER
Report to the Nation: 2003
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Drug Review (continued)
Index
Over-the-counter drug statistics
- 1 new Rx-to-OTC switch
- 2 new uses
We approved one new Rx-to-OTC switch. We approved two
supplemental applications for existing OTC products, one of
which can be used by children. The approvals are:
- Omeprazole magnesium (Prilosec OTC)
is the first
OTC treatment for frequent heartburn in consumers 18 years
of age and older. This previously prescription-only drug
stops acid production at its source in the stomach. It
works differently than the other two classes of OTC
heartburn treatments: antacids and acid reducers.
Famotidine (Pepcid AC) prevents and temporarily
relieves heartburn in consumers 12 years of age and older.
This approval was for a higher OTC dose.
Loratadine hydrochloride (Claritin Hives Relief)
temporarily relieves itching due to hives for adults and
children 6 years and older. This antihistamine was first
approved OTC for the temporary relief of allergy symptoms in
2002. This approval was a new use to be marketed under the
brand name Claritin Hives Relief.
Education campaign on safe use of OTCs
We developed a national education campaign to provide
advice on the safe use of over-the-counter pain and fever
reducers.
The campaign focuses on OTC drug products that contain
acetaminophen and non-steroidal anti-inflammatory agents,
which include products such as aspirin, ibuprofen, naproxen
sodium and ketoprofen.
Many OTC medicines sold for different uses have the same
active ingredients. To minimize the risks of an accidental
overdose, we are trying to educate consumers to avoid taking
multiple medications that contain the same active ingredient
at the same time.
You can learn more about this educational campaign at our
Web site:
http://www.fda.gov/cder/drug/analgesics/.
Improved labels for OTC medicines
American consumers are benefiting from easy-to-understand
labels on drugs they buy without a prescription.
A mandatory changeover to the new labels, titled “Drug
Facts,” began in 2002.
How we regulate OTC drugs
We publish monographs that establish acceptable
ingredients, doses, formulations and consumer labeling for
OTC drugs.
Products that conform to a final monograph may be
marketed without prior FDA clearance.
Drugs can also be approved for OTC sale through the new
drug review process.
More information about the OTC drug review process is at http://www.fda.gov/cder/about/smallbiz/OTC.htm.
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Generic Drug Review
Generic drug statistics
- 263 generic drug approvals
- Median approval time: 17.0 months
- 101 tentative approvals
- 479 receipts
We approved 263 generic drug products in 2003, including
a substantial number of products that represent the first
time a generic drug was available for the brand-name
product. The median approval time for generic drugs was 17
months.
The median statistic for total approval time has hovered
at about 18 to 19 months for six years. We made changes to
decrease the overall time to approval of applications by
three months over the next three to five years. We are
improving the efficiency of our generic drug review process
and increasing the number of chemistry reviewers by
one-third.
Notable 2003 generic drug approvals
Examples of first-time approvals for the brand-name
equivalent drugs are:
(Paxil) used to treat depression.
Gabapentin (Neurontin) used to treat certain kinds
of seizures.
Mirtazapine (Remeron) used to treat depression.
Quinapril (Accupril) used to treat hypertension.
Our approval of generic versions of these drugs last year
could save American consumers and the federal government
hundreds of millions of dollars each year.
Tentative vs. full approval
We also issued 101 tentative approvals. While full
approvals decreased from 321 to 263, the tentative approvals
increased from 63 to 101. The review of an application that
is tentatively approved requires the same amount of work as
a review that results in a full approval.
The only difference between a full approval and a
tentative approval is that the final approval of these
applications is delayed due to existing patent or
exclusivity on the innovator drug product. These and other
legal issues continue to be a challenge to the generic drug
review program.
While tentative approvals represent a full workload for
us, they are only displayed in the chart on the next page
once they are converted to full approvals. For example, some
of the 263 approvals in 2003 represent conversions of
tentative approvals granted in 2003 or previous years.
New law aims to speed approval of generics
Provisions of the Medicare Prescription Drug,
Improvement and Modernization Act of 2003, which became
law on Dec. 3, 2003, are expected to decrease time-consuming
legal delays in the approval and marketing of generic
products.
The law incorporates much of the substance of our final
regulation issued in 2002, particularly the limitation on
30-month stays that may delay availability of generic drugs.
The law codifies several points regarding patent
notification and forfeiture of 180-day exclusivity on the
part of a generic applicant.
We are working on new regulations to implement the law.
Generic drug review efficiencies
Receipts of generic drug application increased more than
one-fifth in 2003 to 479 from 392 in 2002. This dramatic
increase in applications makes it imperative that we have
the ability to process generic drug applications more
efficiently
We are continue to look for ways to improve our process
and also to provide communication and guidance to industry,
with the overall goal of getting generic drug products to
the consumer as efficiently as possible.
We are taking steps aimed at improving the content and
completeness of generic drug applications and assuring that
the applications contain the needed information to be
evaluated successfully in one cycle. These steps include:
- Enhanced communication with individual applicants
during the review process.
- A collaborative effort with the Generic Pharmaceutical
Association to assist the industry. Over the past year,
this project has already resulted in six important
meetings between us and members of the generic drug
industry.
- Two “ANDA Basics” workshops held to assist generic
drug makers in understanding the review process and
provide training on how to prepare a generic drug
application, known formally as an abbreviated new drug
application or ANDA.
- Efforts to encourage submission of applications in an
electronic format for greater efficiency.
Electronic submissions
Through public presentations, we are encouraging the
generic drug industry to submit their applications
electronically.
Increased generic drug review staff
We have constituted a third chemistry review division for
generic drugs. We are augmenting our clinical review staff
to further speed our review of generic drug applications.
How we approve generic drugs
Generics are not required to repeat the extensive
clinical trials used in the development of the original,
brand-name drug.
For many products such as tablets and capsules, the
generics must show bioequivalence to the brand-name
reference listed drug. This means that the generic version
must deliver the same amount of active ingredient into a
patient’s bloodstream and in the same time as the
brand-name reference listed drug.
The rate and extent of absorption is called bioavailability.
The bioavailability of the generic drug is then compared to
that of the brand-name. This comparison is bioequivalence.
Brand-name drugs are subject to the same bioequivalency
tests as generics when their manufacturers reformulate them.
Scientific basis for generic drug review
We have continued to articulate the scientific
underpinnings of our review process and to work to define
mechanisms to evaluate equivalence of certain unique
products.
Consumer communication
Our efforts to build consumer confidence in generic drug
products are continuing through our Generic Drug Quality
Awareness program.
We have partnered with a number of professional and
consumer organizations to launch programs about the quality
and benefits of generic drugs. We have helped design
messages that appear on prescription bags in CVS and Kmart.
We have partnered with Express Scripts to get the word out
to their consumers about the quality and value of generic
products.
Radio public service announcements with the generic drug
quality message will be appearing in several geographic
areas. Our generic drug public service announcements are at http://www.fda.gov/cder/consumerinfo/generic_info/default.htm.
Generic drug Web site
You can find more information about our generic drug
program at http://www.fda.gov/cder/ogd/.
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Assessing Data
Quality, Research Risks
Inspections for data quality, research risks in 2003
We conducted a total of 728 inspections in 2003 compared
to 589 in 2002:
- 324 U.S. clinical investigators
- 44 foreign clinical investigators
- 154 institutional review boards
- 17 sponsors, monitors or contract research
organizations
- 87 good laboratory practices
- 102 in-vivo bioequivalence
When obtaining data about the safety and effectiveness of
drugs, sponsors rely on human volunteers to take part in
clinical studies and high quality laboratory studies.
Protecting volunteers from research risks is a critical
responsibility for us and all involved in clinical trials.
We perform on-site inspections to protect the rights and
welfare of volunteers and verify the quality and integrity
of data submitted for our review. We inspect domestic and
foreign clinical trial study sites; institutional review
boards; sponsors, monitors and organizations conducting
research; laboratories that obtain data; and sites
performing bioequivalence studies in humans (see “How we
approve generic drugs”) and
preclinical studies in animals.
Our programs to protect volunteers are challenged by
increases in the number of clinical trials; the types and
complexity of products undergoing testing; and the increased
number of trials performed in countries with less experience
and limited or no standards for conducting clinical
research.
Sponsors and clinical investigators protect volunteers by
ensuring that:
- Clinical trials are appropriately designed and
conducted according to good clinical practices.
- Research is reviewed and approved by an institutional
review board.
- Informed consent is obtained from participants.
- Ongoing clinical trials are actively monitored.
Special attention is given to protecting vulnerable
populations, such as children, the mentally impaired or
prisoners.
We require sponsors to disclose financial interests of
clinical investigators who conduct studies for them. This
helps identify potential sources of bias in the design,
conduct, reporting and analysis of clinical studies.
Top 5 deficiency categories for clinical investigator
inspections
- Failure to follow the protocol
- Failure to keep adequate and accurate records
- Problems with the informed consent form
- Failure to report adverse events
- Failure to account for the disposition of study drugs
International inspections of clinical research
We have conducted 510 inspections of clinical research in
53 countries from 1980 to 2004. We participate in
international efforts to strengthen protections for human
volunteers worldwide and encourage clinical investigators to
conduct studies according to the highest ethical principles.
These efforts include our work with the International
Conference on Harmonization and the Declaration of Helsinki.
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User Fee Program
Americans deserve timely access to potentially lifesaving
new drugs as soon as possible once they are proven safe and
effective. The Prescription Drug User Fee Act of 1992
received its third five-year extension in 2002, known as
PDUFA III. This reauthorization will help ensure that we
have the expert staff and resources to review applications
promptly and get safe, effective new drugs into the hands of
the people who need them.
PDUFA III maintains the high review performance goals of
PDUFA II and includes increased consultations with drug
sponsors and provided for earlier feedback on their
submissions. Although our resources from PDUFA III are
higher than from PDUFA II, our total resources for new drug
review have not increased as much as we expected.
Under PDUFA II, we collected significantly less in user
fees than estimated due to a reduced number of new drug
applications and an increased proportion of submissions
whose fees were waived. The expectation that the
reauthorization would put the user fee program on a sound
financial basis has only been partially met.
We are concerned about the safety of new medicines
following approval. In recent years, 50 percent of all new
drugs worldwide have been launched in the United States, and
American patients have had access to 78 percent of the
world’s new drugs within the first year of their
introduction.
PDUFA III allows us to spend some user fees to increase
surveillance of the safety of medicines during their first
two years on the market or three years for potentially
dangerous medications. It is during this initial period,
when new medicines enter into wide use, that we are best
able to identify and counter adverse side effects that did
not appear during the clinical trials.
Full information on PDUFA III, including the latest
performance and procedure goals, is on the Web at
http://www.fda.gov/oc/pdufa/PDUFA3.html.
User fee performance
Under legislation authorizing us to collect user fees for
drug reviews, we agreed to specific performance goals for
the prompt review of submissions. We met or exceeded all our
performance goals for the fiscal year 2002 receipt cohort.
We are on track for meeting or exceeding all user-fee
performance goals for fiscal year 2003.
Internet resources for user fees
Our user fee Web site has links to more documents and
information including our user fee performance report to
Congress. The page is at http://www.fda.gov/cder/pdufa/default.htm.
End-of-Phase-2A-Meeting Pilot
Making better use of data collected early in drug
development could help sponsors avoid some pitfalls that
lead to either an extra cycle of review or Phase 4
commitments. We are undertaking a pilot program to discuss
this early data with drug sponsors voluntarily at an
End-of-Phase-2A meeting.
We think this will improve dose selection and study
design for subsequent clinical trials. More information is
available in a concept paper we issued in October 2003 (http://www.fda.gov/ohrms/dockets/ac/03/briefing/3998B1_01_Topic%201-Part%20A.pdf).
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Electronic
Submissions
The number of new drug applications submitted
electronically, the number of participating companies and
the number of applications with electronic components
continues to grow.
The major change last year was the inclusion of two
additional types of submissions that can be provided in
electronic format: investigational new drug applications and
drug master files.
Electronic submissions following the electronic Common
Technical Document specifications provide our reviewers
significant advantages over paper submissions and electronic
submissions following past specifications.
The eCTD allows our reviewers to build a cumulative table
of contents for viewing the entire life cycle of the
applications. The CTD and eCTD standardized table of
contents puts the same information in the same place every
time regardless of application type.
This reduces the amount of time reviewers spend trying to
find where information is located. It not only improves the
efficiency of finding documents but also provides a
comprehensive picture of the changes to the application over
time. This is particularly useful in the efficient reviewing
continuous marketing applications under PDUFA.
Last year, we made further strides in establishing
standards for the submission of clinical and animal toxicity
study data and annotated electrocardiogram waveform data.
We cooperation with outside organizations working to
publish standards for the submission of study data. These
groups include the Clinical Data Interchange Standards
Consortium and the Standard for Exchange of Non-clinical
Data consortium working through Health Level Seven.
We continue to receive individual case safety reports and
other post-marketing reports from manufacturers in
electronic format, including adverse event reports.
All submissions can use eCTD
As of August 2003, we are able to receive all
applications and related submissions in electronic format
following the electronic Common Technical Document
specifications. This includes:
- New drug applications
- Generic drug applications
- Biologics licensing applications
- Investigational new drug applications
- Drug master files
Internet resources
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Antimicrobial
Resistance
The emergence of drug-resistant bacteria is considered to
be a major threat to the public health. We developed a
regulation outlining new labeling designed to help reduce
the development of drug-resistant bacterial strains. This
rule became final in February 2003 and aims at reducing the
inappropriate prescription of antibiotics to children and
adults for common ailments such as ear infections and
chronic coughs.
Details of our other efforts and resources are at http://www.fda.gov/cder/drug/antimicrobial/default.htm.
Antimicrobial resistance education campaign
Last year, we joined with the Centers for Disease Control
and Prevention to launch an education campaign on antibiotic
resistance. The campaign includes print, radio and TV public
service announcements and brochures. We are both now working
on materials for the Spanish-speaking audience.
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Pregnancy labeling
We have reviewed the current system of labeling drugs for
use by pregnant women and are developing an improved, more
comprehensive and clinically meaningful approach.
We are consulting with multiple government agencies,
medical experts, consumer groups and the pharmaceutical
industry to develop this new labeling format.
We are working with medical review divisions and
pharmaceutical companies to update product labels with
available data regarding human pregnancies exposed to drugs
during pregnancy.
Improving knowledge about use of drugs in pregnancy
In many cases, a disease or condition left untreated may
be more harmful to a woman and her fetus or baby than a drug
treatment. To improve our knowledge of how drugs work during
pregnancy and when women are nursing, we have provided
guidance to industry and our reviewers as well as sponsored
research.
- In 2002, we published a final guidance that provides
sponsors with advice on how to establish pregnancy
exposure registries. Registries that prospectively
monitor the outcomes of pregnancies in women exposed to
a specific drug can provide clinically relevant human
data for treating or counseling patients who are
pregnant or anticipating pregnancy.
- We are working to finalize a guidance for our
reviewers on how to evaluate the outcomes of human
pregnancies exposed to drug products during pregnancy.
This guidance was published in draft form in 1999.
- We are working on numerous guidances that address
study design issues for determining the appropriate dose
of a drug for pregnant women and nursing mothers. These
pharmacokinetic studies evaluate the action of a drug
over time during pregnancy and lactation, including the
processes of absorption, distribution, localization in
tissues, biotransformation and excretion.
- We have funded several studies to evaluate whether or
not the dose a drug should be adjusted for pregnant
women. Pharmacodynamic studies evaluate the biochemical
and physiological effects of a drug and the mechanism of
its actions, including the correlation of actions and
effects of a drug with its chemical structure.
- We funded studies to look at specific anti-infective
drug products that would be used to treat specific
bioterrorism agents in special populations, such as
children, women who are pregnant or nursing and the
elderly.
Research on high blood pressure in pregnancy
FDA’s Office of Women’s Health has funded studies to
look at specific antihypertensive agents used to treat high
blood pressure in pregnancy.
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Drug Review Team
We use project teams to perform reviews. Team members
apply their individual special technical expertise to review
applications:
and
immunologists evaluate
the manufacturing processes for biological products to
ensure the continued purity, potency and safety of these
products. They also provide insights to the review team
regarding the mechanism of action and potential and
observed adverse events associated with specific products.
Chemists focus on how a drug is manufactured. They
make sure the manufacturing controls, quality control
testing and packaging are adequate to preserve the drug
product’s identity, strength, potency, purity and
stability.
Clinical pharmacologists and
biopharmaceutists
evaluate factors that influence the relationship between the
body’s response and the drug dose and evaluate the rate
and extent to which a drug’s active ingredient is made
available to the body and the way it is distributed,
metabolized and eliminated. They also assess the clinical
significance of changes in the body’s response to drugs
through the use of exposure-response relationships and check
for interactions between drugs.
Microbiologists evaluate the effects of
anti-infective drugs on germs. These medicines-antibiotics,
antivirals and antifungals-differ from others because they
are intended to affect the germs instead of patients.
Another group of microbiologists evaluates the manufacturing
processes and tests for sterile products, such as those used
intravenously.
Pharmacologists and
toxicologists evaluate
the effects of the drug on laboratory animals in short-term
and long-term studies, including the potential based on
animal studies for drugs to induce birth defects or cancer
in humans.
Physicians evaluate the results of the clinical
trials, including the drug’s adverse and therapeutic
effects, and determine if the product’s benefits outweigh
its known risks at the doses proposed.
Project managers orchestrate and coordinate the drug
review team’s interactions, efforts and reviews. They also
serve as the regulatory expert for the review team and as
the primary contact for the drug industry.
Statisticians evaluate the designs and results for
each important clinical study.
Advanced scientific education
A committee of our scientists oversees a program of
scientific training, seminars, case study rounds and guest
lectures. This multidisciplinary program helps keep our
scientists up-to-date on the latest developments in their
fields and current industry practices.
Scientific training for reviewers
Our systematic, internal training program is based on
core competencies, learning pathways and individual
development plans. The program grew from seven activities
offered in 1997 to more than 40 in science and science
policy. We offer 44 courses in job skills, research tools,
leadership and management. Reviewer participants increased
six-fold, from about 250 in 1997 to 1,500 currently. Last
year, we brought in 40 visiting professors to talk directly
to individual review divisions about critical, new
drug-related research and techniques.
Academics to CDER
Each spring, we collaborate with five local universities
to present special courses on the most critical needs and
interest of our reviewers. Recent topics were:
- 2004: Applying exposure-response concepts to drug
development.
- 2003: Drug safety assessment tools.
- 2002: Pharmacogenetics.
- 2001: Assessment of QT prolongation (cardiac
arrhythmia) in drug development.
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Date created: May 24, 2004