News Along the Pike
November 10, 2005
Volume 11, Issue 2
Center for Drug Evaluation and Research
Index
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Center ceremony honors 107
individuals, 47 groups: Spring event inaugurates
Frances Kelsey Drug Safety Award
By Jackie Barber Washington
During CDER’s Spring Honor Awards Ceremony, the
Center’s top managers presented 107 individual awards and 47 group or team
awards. Kevin Barber sang the National Anthem. Pat Gathers, from the
Office of Management, was the mistress of ceremonies. Center Director Steven
K. Galson, M.D., MPH,
and Deputy Center Director Douglas Throckmorton, M.D., presented the awards
along with CDER’s senior staff.
“I am very pleased to have established
the Dr. Frances O. Kelsey Drug Safety Excellence Award and to recognize the
first recipients for their outstanding accomplishments in this important aspect
of drug regulation,” Dr. Galson noted. “I am inspired by the dedication and
commitment of our talented staff.”
Click here to read the awards.
Jackie Barber Washington is the Center’s incentive awards
officer.
Office of Biotechnology
Products tackles transition
By Steven Kozlowski,
M.D.
With the move of CDER’s reviewers to White Oak this
summer and fall, the clinical review of therapeutic biological products has
become formally integrated into the Center’s traditional discipline-oriented
structure. Because our office—the Office of Biotechnology Products—has primary
review responsibility for therapeutic biologics quality issues and will remain
in Bethesda, we want to take this opportunity to introduce the rest of CDER to:
Biologics A to Z
When oversight of therapeutic biologics officially
transferred to CDER in 2003,
review responsibilities were divided between the Office of New Drugs and the
Office of Pharmaceutical Science.
Our office—the Office of Biotechnology
Products in OPS—has primary review responsibility for chemistry, manufacturing
controls and product quality.
We have approximately 60 licensed
products from Activase (alteplase) to Zevalin (ibritumomab tiuxetan). Among them
are:
- Erythropoetins, widely used for
treatment of anemia induced by chemotherapy and renal disease.
- Interferons, used for a number of
different indications from malignancy to hepatitis.
- Fusion proteins and antibodies that
target inflammatory mediators, such as tumor necrosis factor.
- Monoclonal antibodies that target
molecules on the surface of tumor cells. Examples are antibodies targeting
epidermal growth factor receptor and Erb2.
These products improve survival times
and/or quality of life in a variety of diseases, and there are hundreds of new
products under development. Despite an overall slowing in development of new
molecular entities, many biotechnology product classes have an increasing
product pipeline.
Biotechnology products comprised
approximately $30 billion of the $400 billion in worldwide pharmaceutical sales
in 2002. The biotechnology percentage of worldwide pharmaceutical sales is
increasing. Estimates of biotechnology are that sales in 2004 exceeded $40
billion dollars. In addition to their current role as monotherapy, proteins are
likely to play important future roles in combination therapies and in
conjunction with cellular and nano-technologies.
Product quality scientific issues
There are a large number of scientific issues in the
manufacture and quality control of therapeutic proteins. Unlike many small
molecule drugs, often our products cannot be fully characterized using
traditional physical or chemical methods. For many of our products, it is
infeasible to have a complete evaluation of product’s structure or even how many
active molecules it contains.
This leads to complex regulatory
decisions regarding “sameness” of protein therapeutics. These issues extend
beyond protein chemistry into broader areas of protein function and biology.
Often, comparability is a relative
assessment that requires information on the amount of clinical and pre-clinical
information being transferred from the old to the new version of the product.
Successful science-based regulatory decisions have depended on and will continue
to depend on close interactions between the review disciplines.
Importance of manufacturing controls
The difficulties in characterizing therapeutic
proteins have led to a greater dependence on a controlled manufacturing process.
Because of the importance of facilities in a consistent manufacturing process,
the Therapeutics Facilities Review Branch in the Office of Compliance plays a
significant role in the evaluation of biotechnology products
(July 2004
Pike).
The important role of process in all
pharmaceutical manufacturing is being recognized with initiatives such as cGMPs
for the 21st Century and Process Analytical Technology. Although biotechnology
product manufacturing has historically focused on process, there are many areas
for improvement with real-time monitoring and control of both critical process
parameters and product attributes.
Inherent to these improvements is an
understanding of the important product attributes for safety and efficacy. This
is a very challenging task for all products and especially for complex mixtures
of proteins. The biological characterization of proteins and the understanding
of structure and function relationships are important in making informed
decisions.
Because of the lack of certainty
regarding structure, biological tests are commonly used to evaluate our
products. Ideally, these assays should reflect the molecular mechanism of
action. Knowledge about a product’s mechanism of action is important for
regulating applications in a context broader than the assessment of
manufacturing quality.
Role of molecular mechanisms
Molecular mechanisms cannot replace clinical data but
may be of value when there are inadequate clinical data to make a decision.
Shared mechanisms may alert us to potential adverse events. For many therapeutic
proteins, adverse events are due to the primary mechanism of action. Therefore,
mechanistic information can provide a critical context for informed decisions
regarding product safety.
In some cases, mechanistic information
can facilitate selection of relevant animal models and speed products along the
Critical Path (July 2004 Pike).
Many of our reviewers are biologists and some are pharmacologists or physicians.
In addition, many of our reviewers
perform bench research and publish in areas related to the products they review.
A list of contacts for mechanistic and technical issues has been placed on our
intranet site
(http://cdernet.cder.fda.gov/ops/opsdiscp.htm)
and distributed to the review divisions.
In the future, advances in systems
biology will allow for more “personalized medicines”
(April 2005 Pike)
and facilitate clear decisions on drugs with far smaller numbers of patients
needed in clinical trials. The understanding of biological mechanisms can
facilitate use of data sets such as those provided by proteomics or
pharmacogenomics.
In many clinical studies, the numbers
leading to an association of a clinical outcome with a set of markers may not be
statistically convincing. The mechanistic context of these markers, however, may
add confidence to their validity and further use.
We can play a role in helping you make
an assessment of biological plausibility. Therefore, we have begun planning
interactions with the Interagency Pharmacogenomics Review Group
(April Pike).
Immune system responses
Another important issue relevant to protein
therapeutics is their potential to be recognized as foreign by a patient’s
immune system. In some cases, immune responses to a protein product have led to
neutralization of the patient’s own version of the protein.
In the case of erythropoetin, for
example, such immune responses have left some patients unable to make red blood
cells, a condition known as transfusion-dependent pure red cell aplasia or PRCA.
Of note, increased occurrences of PRCA were associated with a manufacturing
change of the product distributed in Europe.
Improved communications
This reinforces the strong
relationship between clinical and manufacturing review disciplines. Our office
has many experts in immunology who are well-known in both academia and industry.
They are a valuable resource for
general approaches to immunogenicity and for evaluation of assays to detect
immunogenicity.
We also will be placing our point of
contact for immunogenicity issues on our intranet site and passing it out to
Center offices and divisions.
Although most of CDER’s review staff
has moved to White Oak, our offices and labs will remain on the NIH campus in
Bethesda for a few more years. Although there are many advantages to having
access to NIH researchers, conferences and libraries, we will have some
challenges in communicating with other parts of CDER. From collaborating with
two clinical divisions in one office, we will now need to communicate with 13
divisions in five offices.
We plan to have primary and secondary
contacts for assignments. Once assigned, our reviewer will be the primary
contact for product-related questions.
In addition, we have assigned each OND
office an umbrella contact who will spend one day a week at White Oak. Details
on these contacts are also included on our intranet site
(http://cdernet.cder.fda.gov/ops/opsdiscp.htm).
We are interested in feedback on our
interactions with other offices in CDER. We look forward to working closely with
you to ensure that quality pharmaceutical products are available to the public.
Steven Kozlowski is acting director of the Office of Biotechnology Products.
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Regulation requires
electronic Structured Product Labeling
A regulation effective Nov. 2 requires drug
manufacturers to submit prescription drug label information in an electronic
format. Called Structured Product Labeling, or SPL, this format will allow
health-care providers and the general public easier access to the product
information found in the FDA-approved package inserts, or “labels,” for all
approved medicines in the United States.
The new electronic product labels will
be the key element and primary source of medication information for DailyMed.
This interagency online health information clearinghouse will provide the most
up-to-date medication information free to consumers, health-care providers and
health-care information providers. Within one year, product labels for most
approved prescription medications will be posted on DailyMed.
DailyMed will be accessed through the
National Library of Medicine at
http://dailymed.nlm.nih.gov. In the future,
this new product information will also be posted on a comprehensive Internet
resource—Facts@fda.gov—that will give one-stop access to information about all
FDA-regulated products.
The SPL project, led by CDER, is the
first in an Agencywide initiative regarding the public provision of electronic
information. In the future DailyMed also will include labels for biologics (such
as vaccines), medical devices, veterinary drugs and some food products. The
agency expects to launch additional components of the facts@fda.gov Internet
resource early next year.
“Providing health-care providers and
patients with clear, concise information about their prescriptions will help
ensure safe use of drugs and better health outcomes,” said Health and Human
Services Secretary Mike Leavitt. “Now medication information will be easy
to access on a publicly available Web site, and this will lead to future
innovations with health information technology.”
Under the new regulation, drug
manufacturers are required to submit prescribing and product information in SPL
format. This accessible, computer readable format will help provide accurate,
up-to-date drug information using standardized medical terminology.
Using embedded computer tags, the
prescribing and product information in SPL can be electronically managed,
allowing searches for specific information. These tags can instruct computers to
read specific sections of a drug label including product names, indications,
dosage and administration, warnings, description of drug product, active and
inactive ingredients and how the drug is supplied.
With this information, physicians will
be able to quickly search and access specific information they need before
prescribing a treatment.
In addition, having the labels
submitted in SPL will improve the drug labeling review process. In turn, we can
provide doctors and patients faster access to the most recent information about
medications.
As FDA receives SPL-formatted
labeling, health-care professionals, patients, online information providers and
other consumers will be able to access the newly updated labels on the Internet,
free of charge through the DailyMed system.
Updated product labels will be posted
on the site within one business day of either an approval action or a submission
of a labeling change that does not require an approval.
“This unprecedented health technology
partnership builds a solid foundation for enhanced e-health initiatives to be
realized in the very near future,” said Acting FDA Commissioner Andrew von
Eschenbach, M.D.
“The electronic standards established
with structured product labeling pave the way for future health information
innovations in areas such as electronic prescribing and electronic health record
keeping, that can transform the way we gather, use and share medication
information from bench to bedside.”
The DailyMed system was developed in
collaboration with federal agencies including: FDA, the National Library of
Medicine, the Agency for Healthcare Research and Quality and the National Cancer
Institute in the Department of Health and Human Services and the Veterans Health
Administration in the Department of Veteran Affairs.
The SPL initiative is part of an
ongoing collaboration of federal agencies to apply modern principles of
information science to translate, repackage and freely distribute up-to-date
medication information in a reliable, accurate and consistent format. The group
is dedicated to building a nationwide infrastructure for managing medication
information to improve healthcare quality in the United States.
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CDER’s small business
workshop in Kansas City draws 125
By Ron Wilson
The Center and FDA’s field operations co-sponsored a
workshop in May in Kansas City for 125 representatives from the small
pharmaceutical business community. The meeting provided small businesses with
the opportunity to dialogue with subject matter experts from CDER and FDA’s
Office of Regulatory Affairs and gain an understanding of the regulatory
requirements for approval and marketing of drug products. Regulatory compliance
and other issues also were on the agenda.
This meeting was the second of its
kind. Although the workshop was in the mid-West, attendees came from all parts
of the country. We are working on holding a similar small pharmaceutical
business workshop in Washington in the spring.
The topics and speakers were:
- Introduction, John A. Friel, deputy director, Office of Training and Communications.
- Planning for successful, efficient,
pharmaceutical product approval, Kim
Colangelo, associate director for
regulatory affairs, Office of New Drugs.
- Current challenges and concerns for
generic abbreviated new drug applications, Martin Shimer,
branch chief, Regulatory Support Branch, Division of Labeling and Program
Support, Office of Generic Drugs.
- Regulatory aspects and challenges in
the development of over-the- counter drugs, David Hilfiker, supervisory project manager, Division of
Nonprescription Clinical Evaluation, Office of Nonprescription Products.
- The basics of chemistry,
manufacturing and controls, Ramnarayan
Randad, chemist, Division of Chemistry I,
Office of Generic Drugs.
- Top regulatory issues in the drug
industry, John Thorsky,
ORA Kansas City district director.
- Mastering regulatory compliance, Thomas Arista, national expert, ORA Division of Field Investigations.
- Federal financial incentives and
assistance for small businesses, myself.
- The ORA small business
representative program, David Arvelo, ORA Southwest Region small business
representative.
Ron Wilson is the director of CDER’s small business assistance in OTCOM.
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Pharmaceutical Inspectorate
completes training for 23 field inspectors
By Patrick E. Clarke
The Pharmaceutical Inspectorate training program
graduated its first group of 23 field investigators in August. The program is a
part of the strategic initiative to overhaul pharmaceutical regulatory and
quality control systems
(http://www.fda.gov/cder/gmp/).
“The program gives investigators more
specialized, advanced training and the opportunity to interact with other
regulatory and review offices within the Agency,” said Karen Hirshfield,
R.Ph., a compliance officer in the Office of Compliance’s Division of
Manufacturing and Product Quality. Hirshfield is on the Pharmaceutical
Inspectorate Course Advisory Group and the Level III Drug Investigator
Certification Board.
The course advisory group—11
representatives from FDA’s Office of Office of Regulatory Affairs, CDER and the
Center for Veterinary Medicine—developed the curriculum. “Process analytical
technology, facility design and statistics used at pharmaceutical manufacturing
sites are just some of the areas covered in the last training module,
technology,” Hirshfield said.
The curriculum, which took more than a
year to develop, included topics in:
- Risk management.
- Advanced quality systems.
- Current regulatory programs and
procedures.
- Investigational techniques.
- Pharmaceutical science.
“It has been challenging to create the
training program because it is brand-new and had to be developed from scratch,”
Hirshfield said.
Some of the criteria required for an
investigator to go through the pharmaceutical inspectorate program include three
years of experience in drug inspections and a Level II certification from ORA’s
Drug Investigator Certification Board.
The investigator must have district
office approval and participate in a detail in either the Office of Compliance
or the Office of Pharmaceutical Science. Many details are ongoing. “The details
allow the investigators to be involved in the daily activities of the CDER
offices in order to gain a better appreciation for what we do,” Hirshfield said.
Three one-week training blocks are
needed to complete the curriculum. The first block was held at the ORA
University in August 2004. Compliance officers from CDER, ORA and CVM and
reviewers from CDER and CVM participated in the training for a total of
approximately 70 FDA employees.
“We’re trying to foster interaction
between investigators and compliance officers and chemistry reviewers,”
Hirshfield said.
The second week of training was held
during the first week of February and the last training week was in August.
“The last week focused on technology,
but we pulled together concepts taught in previous blocks,” Hirshfield said.
“For example, lessons in solid oral dosage form manufacturing also addressed how
risk and quality principles apply.”
Speakers for the courses have come
from inside FDA, academia, industry and outside consulting firms.
“Some of the inside speakers have been
top managers including Janet Woodcock, M.D., David Horowitz and Helen
Winkle along with top ORA managers,” Hirshfield said.
The goal agreed upon between CDER and
ORA was that a total of 50 investigators will have completed the program by
fiscal year 2007. Planning for selecting the next group of investigators and for
the training course program is underway.
“The program is beneficial for
investigators, reviewers and compliance officers,” Hirshfield said, “and the
interaction will streamline the process of putting inspectional information to
the best use possible.
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DARRTS: Integrated document database
targets therapeutic biologics INDs
By Virginia Ventura
If you’re a biologics reviewer, you will soon be
pioneering a new software program called DARRTS. No, not the little pointy
things you throw, but a system that will ultimately act as the Center’s main
repository of regulatory documents.
DARRTS stands for Document Archiving,
Reporting and Regulatory Tracking System. This single, integrated system will
eventually house many of the Center’s core tracking systems, such as:
- Components of the Centerwide Oracle
Management Information System or COMIS.
- The Division Files System or DFS.
- CDER Standard Letters or CSL.
However, the first release of DARRTS,
planned for this winter, will target only investigational new drug applications
for therapeutic biologic products. Only reviewers and project managers working
on biologics IND reviews—primarily former users of the Biologics Investigational
New Drug Management System—will use the software in this first release.
(Unfortunately, there is a great deal
of overlap between the therapeutic biologic IND numbers and older, existing IND
numbers for drugs. On Nov. 11, current CDER INDs numbered 14,000 and below will
be renumbered by taking the existing IND number and adding 80,000 to it. Most
CDER INDs in that number range are largely withdrawn, terminated or otherwise
inactive.)
Over the next couple of years, DARRTS
will be expanded to all users throughout the Center and will cover most other
submission types, including new drug applications, generic drug applications,
biologics license applications and other investigational new drug applications.
The DARRTS working group at CDER has
collaborated closely with developers over many months to craft this completely
redesigned database.
The new system strives to allow you
greater flexibility and eliminate some of the familiar work-arounds that you
have had to grapple with.
A sampling of DARRTS highlights
includes:
- Web-based, single sign-on.
- Application numbers automatically
generated.
- Incoming document data entry done by
document room (except for single-patient INDs with authorization).
- Division staff ability to create
emergency INDs.
- All updates based on transmittal form
information or project manager notifications performed by document room staff,
not reviewers.
- Goals, statuses, assignments and other
standard data automatically maintained by system.
- No system codes to memorize or worry
about deciphering.
Information on training will be
conveyed by e-mail, and all training materials will be posted on the CDER
intranet. Training will consist of two parts:
Conceptual training, to be held in the
mornings.
Classroom demonstration, usually in the
afternoons.
Since DARRTS concepts are so different
from those used by the current systems, it’s important for you to attend the
conceptual session and to ask questions of the experts. The classroom
demonstration that follows will take into practice the points discussed in
conceptual training. There will be a total of 10 overall training sessions, open
to reviewers involved with biologics INDs.
For more information on DARRTS
training please contact me at 301-796-1016 or e-mail
Virginia.Ventura@fda.hhs.gov.
For information on the DARRTS project
in general, contact Linda Sigg at 301-796-0625 or
Linda.Sigg@fda.hhs.gov.
Virginia Ventura is a member of the Regulatory Review Support Staff in the
Office of Business Process Support Staff.
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Information
Technology Corner: New version of Substance
Registration System key to structured labeling
By Binh Ta, Colleen
Ratliffe
and Sandra Valencia
A new version of the Substance Registration
System/Ingredient Dictionary soon will be available for use as a key component
of the Structured Product Labeling program
(above).
The dictionary has been designed to
enable FDA to efficiently, effectively and reliably maintain unique identifiers
for substances in drugs, biologics, foods and devices.
When implemented, the system will help
FDA and the medical communities standardize substance data by generating the
Unique Ingredient Identifier.
This identifier will be incorporated
into labeling submissions through FDA’s Electronic Labeling Information
Processing System. That system will modernize the way labels are submitted,
reviewed and distributed. The public will access labeling through the National
Library of Medicine’s Web site.
The overall purpose of the structured
product labeling program is to improve patient safety by ensuring that the most
up-to-date medication information is available to health-care providers,
patients and the public. The project is part of a larger initiative called the
DailyMed. The DailyMed Initiative, supported by the Agency for Healthcare
Research and Quality, is a partnership between FDA, medication manufacturers and
distributors, the National Library of Medicine and health-care information
suppliers.
For more information on FDA’s
Substance Registration System, please go to the FDA Data Standards Council
intranet site at
http://intranet.fda.gov/oc/fdadatacouncil/proj.htm
and click on the Vocabulary Standards link at the bottom of the page.
Binh Ta, Colleen Ratliffe and Sandra Valencia are IT specialists in the Office
of Information Technology.
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Pharm/Tox Corner: Biomarker imaging,
laboratory study audits on topic list for retreat
By Gary P. Bond, Ph.D., DABT
The semi-annual scientific retreat for pharmacology
and toxicology reviewers in the Office of New Drugs in March 2 focused on:
The retreat started with opening
remarks from co-chairs Haleh Saber-Mahloogi, Ph.D., and John Leighton
Ph.D., DABT. David Jacobson-Kram, Ph.D., DABT, OND’s associate director for
pharm/tox, welcomed all to the meeting and got it underway.
Biomarker imaging
Biomarker imaging in drug development and licensed
products. George Mills, M.D., Director of the Division of Medical
Imaging and Hematology Products, discussed biomarker imaging as it relates to:
- FDA’s Critical Path Initiative.
- Current and translational biomarker
imaging.
- The association between biomarker
imaging and drug development.
- Successful biomarker development.
- Development of the draft guidance, Exploratory IND Studies,
for biomarker imaging.
As the intent of the Critical Path
Initiative is to improve and speed up drug development, FDA and the National
Cancer Institute interagency imaging initiatives are being developed as well as
other FDA collaborations in biomarker and PET imaging development. Current
biomarker imaging includes pharmacokinetic studies with whole-body imaging for
radiation dosimetry and organ biodistribution as well as targeting of select
organs.
Translational biomarker whole-body
imaging research provides opportunities to confirm preclinical assessments and
to allow an enrichment of the early drug candidate selection process. Challenges
for comparative biomarker whole-body imaging over multiple days include
radiolabel selection, radiolabeling techniques and effective archiving of
imaging results for current and future review and analysis. Safety issues are
evaluated in current, successful biomarker imaging. Such issues include
radiation injury risk to adjacent organs from radiation therapy exposure.
Imaging-based exploratory INDs,
according to the draft guidance, would require limited preclinical development
for proof-of-concept imaging because they expose subjects only to microdoses of
the investigational drug. These studies could facilitate rapid portfolio
assessment and result in an earlier separation of potential “winner and loser”
investigational products. Issues still being addressed in the regulatory
development of imaging biomarkers include whether imaging biomarkers should be a
separate diagnostic IND or be developed within the investigational therapeutic
agent’s IND. The draft guidance is available at
http://www.fda.gov/cder/guidance/6384dft.htm.
Good laboratory practice
Study audits and inspection process/compliance
program. C.T. Viswanathan, Ph.D., associate director of the Division
of Scientific Investigations, provided an overview of CDER’s good laboratory
practice inspection program. These inspections support CDER’s pharm/tox review
process by verifying the nonclinical safety data.
Dr. Viswanathan highlighted the
program’s support of the decision-making process during the drug review with
several case studies. These described the importance of:
- Determining the actual dose of the test
article administered to study animals, specifically relating the ensuing
toxicity or lack of it.
- Following the protocol, including all
required elements in final reports.
- Selecting appropriate doses for
genotoxicity testing.
The significance of test article
characterization information and the results of dose formulation testing were
discussed. Repeated violations of the regulations and non-compliance can lead to
disqualification of a facility based on this program’s risk-based management.
The study directors of nonclinical
studies play a central role. While they can delegate technical responsibilities
to other team members, they cannot delegate the overall responsibility for the
conduct of the study.
Good laboratory practice requirements
outside the United States were discussed, specifically those of the Organization
for Economic Co-operation and Development. The OECD publication on the
organization and management of multi-site studies was used to distinguish the
test facility as the central unit and the multiple test sites with specialized
expertise that conduct portions of GLP studies, as this is the current practice
in many GLP studies. Effective communication between involved parties is
essential and can eliminate potential problems in such studies.
Guidance updates
Safety Testing of Metabolites guidance.
Aisar Atrakchi, Ph.D., a pharmacologist in the Division of Psychiatry
Products and co-chair of the Pharmacokinetic and Toxicokinetic Subcommittee of
the Pharmacology and Toxicology Coordinating Committee, presented an overview
of the draft guidance.
This draft document recommends the
testing of “unique” human metabolites—those found only in humans—or “major”
human metabolites—those found in disproportionately high levels in humans
relative to the test animals. These metabolites may not be adequately tested in
standard nonclinical studies because they did not occur or were present at very
low levels in the animal species used during standard nonclinical toxicology
evaluation.
The draft guidance addresses mainly
metabolites detected in human plasma that represent greater than 10 percent of
administered dose or systemic exposure, whichever is less. Dr. Atrakchi
discussed the general considerations on metabolite identification, study design,
type of nonclinical studies required and timing of when to conduct these studies
in relation to clinical development are discussed.
Genotoxic Impurities guidance. Tim
McGovern, Ph.D., a supervisory pharmacologist in the Division of Pulmonary
and Allergy Products, discussed issues related to genotoxic impurities in drug
substances and products. He included a review of relevant International
Conference on Harmonization guidances and a recent proposal by the European
Medicines Agency as well as an overview of recent experiences and practices
regarding genotoxic impurities within the Office of New Drugs. In addition, he
discussed some initial concepts included in a draft CDER guidance on this topic.
Exploratory INDs guidance. Dave Green,
Ph.D., the ODE I and Office of Antimicrobial Products associate director for
Pharm/Tox, presented the exploratory IND as part of the Critical Path
Initiative. This novel approach to INDs is intended to facilitate the
identification of new approaches to the diagnosis and treatment of disease and
specific, new drug candidates. Although minimizing the use of resources to
identify risk, it maintains standards of patient safety that are consistent with
traditional INDs. Three different examples of exploratory INDs were presented.
The featured INDs demonstrated the application of the concept to the study of
diagnostic imaging and pharmacokinetics, pharmacology and mechanisms of actions
for drug and biologic products.
Case studies on metabolite guidance
Two case studies on the metabolite
guidance were presented:
Tim Robison, Ph.D., DABT,
from the Division of Pulmonary and Allergy Products, presented an example of a
drug that is metabolized to form a unique human metabolite not found in
significant levels in rodents.
This unique human metabolite was found
to be positive in two genetic toxicity assays. In other words, the metabolite
has a potential to damage DNA. There were concerns that rodent carcinogenicity
studies with the parent drug would not assess the cancer-causing potential of
the metabolite. Designs of rodent carcinogenicity studies with the isolated
metabolite were discussed.
Fred Alavi, Ph.D.,
from the Division of Metabolisn and Endocrinology
Products, discussed toxicology issues related to a nitro degradant/impurity
produced during wet granulation (0.3 percent) for which the sponsor wished to
set a 1 percent manufacturing specification.
The structural activity relationship
analysis found the degradant to be strongly positive for genotoxicity and
carcinogenicity. The genotoxic potential of the degradant was confirmed by
standard genotoxicity tests.
Because a human diet rich in nitrates
and acidic stomach environment mimic the prerequisite conditions for nitro
degradant formation, tests were performed to determine the nitro degradant
concentrations in humans. It was discovered that approximately 10 percent of the
parent drug was converted to nitro degradant in vivo.
Because the genotoxic degradant was
produced at relatively high concentrations in humans, but not in rodents due to
the differences in the diet nitrate content, carcinogenicity testing of the
degradant was recommended.
OND updates and Q&A
John Jenkins, M.D.,
director of the Office of New Drugs noted that the office deserves
congratulations for doing an outstanding job, and this is starting to be
recognized by people outside of CDER.
A few additional full-time employees were added in
fiscal year 2005, and they were assigned where the need was the greatest.
Drug safety communications.
OND has had a primary focus on drug safety and
will be looking at how it manages and communicates issues to the outside world.
Some changes will deal with how we get external input, how we communicate with
the public and how we interact with the Office of Drug Safety. While we had a
public advisory committee meeting and followed those recommendations dealing
with Vioxx, doctors and patients should have had better information about the
cardiovascular risk information, Dr. Jenkins said. We will become more
transparent in communicating and sharing post-approval drug risks. Information
asymmetry is a new role for us, and we will become more proactive.
Process improvement.
The guidance document dealing with Good Review Management Principles spells out
the FDA’s expectations for management of the review of new drug applications.
While FDA is the gold standard for the world, that doesn’t mean we can’t improve
on performance. We need to be more effective and efficient, because we can’t
control our workload. An independent consultant did an analysis and came up with
recommendations for process improvement. We are now working on the transition
during the reorganization and need to focus on 4 areas of process improvement
(Meeting Management; Implementation of GRMPs; Post Marketing Safety Data and
Post Approval Labeling Changes; and Updating of Processes and Procedures that
feed into GRMPs)
Quality systems activities.
Discussed previously, these principles (say what you do, do what you say, prove
it, improve it), dovetail with GRMPs. We will continue to improve consistency
and administration of activities, especially across divisions. Examples include,
approaches for the large molecules that have been merged into CDER and
guidances.
Retreat committee
The retreat was organized by pharm/tox reviewers and
staff from various divisions at CDER including: Siham Biade, Gary Bond, Luan
Lee, John Leighton (co-chair), Haleh Saber-Mahloogi (co-chair),
Yanli Ouyang, Tom Papoian, Tim Robison, Lilliam Rosario and Adele
Seifried.
Gary Bond is a pharmacologist in the Division of Pulmonary and Allergy Products
and would like to acknowledge the assistance of speakers and retreat committee
members in the preparation of this article.
Return to Index
CDER 2004 Report to the
Nation now available
in printed version
The Center’s annual compilation of performance
statistics, program descriptions and initiatives is available in a printed
version. We have several hundred copies that we can mail out on a first-come,
first-served basis.
If you are interested, please send an
e-mail with a complete mailing address to
dpapubs@cder.fda.gov.
You can find a Web-readable version of
the report, a printable version and slides of the charts at:
Return to Index
Joe's Notebook: NCTR to study liver toxicity
biomarkers
FDA’s National Center for Toxicological Research and
BG Medicine, a Massachusetts-based biotechnology research company, have agreed
to collaborate on jointly conducting a liver toxicity study. The Liver
Toxicology Biomarker Study is designed to overcome one of the primary obstacles
to the efficient development of safe and effective drugs. It aims to discover
biomarkers of human hepatotoxicity in the standard tests used by pharmaceutical
manufacturers in the initial stages of drug development.
Liver toxicity is the most common
biological reason for drug failure in the development of new pharmaceuticals. It
affects one in six drugs in development. The toxicity tests currently in use by
drug companies have been unchanged for at least 40 years and often fail to
identify human liver toxicity issues. Consequently, liver toxicity is often
detected for the first time when drugs are in Phase 2 of clinical testing after
tens of millions of dollars or more have been spent on a drug’s development.
Early detection of potential safety
problems is one of the main objectives of the Critical Path Initiative, which
seeks to modernize drug development by making the process more predictable,
successful and less costly. The proposed project addresses the liver toxicity
issue highlighted in the Critical Path document as one of the obvious and
priority areas for innovation.
“Liver toxicity is a common reason for
drug development failure,” said FDA Deputy Commissioner for Operations Janet
Woodcock, M.D. “In part, this is due to the fact that the safety evaluation
relies on decades-old technologies that may recognize safety problems only after
extensive clinical studies. By identifying biomarkers for liver toxicity at the
start of the development process, this research should yield important benefits
for industry, the FDA and the public.”
Dr. Woodcock is the principal author
of FDA’s March, 2004 report, Innovation/Stagnation: Challenge and Opportunity
on the Critical Path to New Medical Products.
The CRADA procedure routinely governs
FDA’s collaborative studies with the private sector. The Liver Toxicity
Biomarker Study has been designed by FDA and BG Medicine with input from other
pharmaceutical companies and will be conducted, with their collaboration, at the NCTR laboratory in Jefferson, Ark., and BG Medicine in Waltham, Mass.
Participating companies will receive
access to all project data and a perpetual license to any biomarkers that are
discovered.
————————————————
Corrections.
Some photocopies and the initially posted Internet
versions of the April News Along the Pike, contained errors in the awards
listings.
In the story about the FDA Science
Forum, some incorrect information appeared for Joan Buenconsejo, Ph.D.,
who was nominated by CDER for the Outstanding Junior Investigator Award.
In the main awards story, Gregory
M. Dubitsky, M.D., received a CDER Excellence in Mentoring Award and
Robert Harris, M.D., received a CDER Excellence in Leadership Award. The
names and awards had been inadvertently reversed. The Internet versions are now
correct.
————————————————
Dec. 1: World AIDS Day.
An estimated 39.4 million people worldwide were
living with HIV at the end of 2004, and more than 20 million people have died of
AIDS since 1981. With more than 1 million HIV-positive individuals in the United
States and 35,000 to 40,000 new infections every year, our country, like other
nations around the world, is deeply affected by HIV/AIDS. HHS encourages you to
visit its Web site and download World AIDS Day educational materials at
http://www.omhrc.gov/hivaidsobservances/world/.
Return to Index
Editorial board
The Pike is published electronically approximately
every other month on the World Wide Web at:
http://www.fda.gov/cder/pike.htm.
Photocopies are available in the FDA Biosciences Library in the
Parklawn Building, Room 11B-40, and its White Oak Branch on the
ground floor of Building 22, Room 0443.
Views and opinions expressed are those of the authors and do not
necessarily reflect official FDA or CDER policies. All material in
the Pike is in the public domain and may be freely copied or
printed.
Rose Cunningham
Pam Fagelson
Elaine Frost
Mary Jane Mathews
Edward Miracco
Melissa Moncavage
Ellen Shapiro
Ted Sherwood
Tony Sims
Nancy Smith
Wendy Stanfield
Marcia Trenter
Jennifer Wagner
Diane Walker
Grant Williams
Pamela Winbourne
Have ideas, news or comments to contribute? Please
contact a member
of the Editorial Board or:
News Along the Pike
CDER Office of Training and Communications (HFD-210)
Parklawn Building, Room 12B-31
Editor:
Norman "Joe" Oliver
(OLIVERN)
Associate Editors: Patrick Clarke, Sherunda Lister
Phone: (301) 827-1695
Fax: (301) 827-3055
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Date created: November 10, 2005
