Food and Drug Administration
(FDA): FDA overview and
Bioresearch Monitoring
CDR Tejashri Purohit-Sheth, M.D.
Branch Chief, Good Clinical Practice II
Division of Scientific Investigations
Center for Drug Evaluation and Research
Food and Drug Administration
Outline
•
•
•
•
FDA Overview
History
Product Development Process
Bioresearch Monitoring
Our New
Campus
FDA Mission
• “The FDA's mission is to promote and
protect the public health by helping safe
and effective products reach the market in
a timely way, and monitoring products for
continued safety after they are in use. Our
work is a blending of law and science
aimed at protecting consumers.”
FDA Responsibilities
• protecting the public health by assuring the
safety, effectiveness, and security of
– human and veterinary drugs, vaccines and other
biological products, medical devices, our nation’s food
supply, cosmetics, dietary supplements, and products
that give off radiation
• advancing the public health by helping to speed
product innovations
• helping the public get the accurate, sciencebased information they need to use medicines
and foods to improve their health
FDA Regulates
• foods, except for most meat and poultry products, which are
regulated by the U.S. Department of Agriculture
• food additives
• infant formulas
• dietary supplements
• human drugs
• vaccines, blood products, and other biologics
• medical devices, from simple items like tongue depressors, to
complex technologies such as heart pacemakers
• electronic products that give off radiation, such as microwave ovens
and X-ray equipment
• cosmetics
• animal feeds and drugs, and devices used in pets, farm animals,
and other animals
• tobacco products
History
History
• Harvey Wiley – chief chemist in Division of
Chemistry in Department of Agriculture
Bureau of Chemistry (1901)
• Bureau examined chemicals with the aim
of standardizing analyses for quality and
consistency
*FDA: A Century of Consumer Protection – FDLI publication for the FDA Centennial +
FDA’s Centennial History sites
History
• 1902 Biologics Control Act (later called
Public Health Service – PHS – Act)
– 1901 = death of 10 children after contracting
tetanus from horse anti-diphtheria antitoxin
– Regulated sale of viruses, serums, toxins, and
analogous products
– Authorized biologics regulations
– Required licensing of manufacturers and
establishments
– Provided inspection authority
History
• Pure Food and Drugs Act of 1906
– Passed due to shocking disclosures of
insanitary conditions in meat packing plants,
use of toxic preservatives in dyes and foods,
and cure-all claims for dangerous patent
meds
– Act prohibits interstate commerce of
misbranded and adulterated foods, drinks,
and drugs
– Manufacturer not required to submit evidence
of drug safety or efficacy
History
• Pure Food and Drugs Act of 1906 (cont.)
– Permitted government to take action if a drug
proved too dangerous or misbranded
– 1911 Supreme Court judgment = Act did not
prohibit false therapeutic claims, only false
and misleading statements about the
ingredients or identity of a drug
•
•
History
1912 – Sherley Amendment prohibits
labeling medicines with false therapeutic
claims intended to defraud the consumer
1927 – Bureau of Chemistry reorganized
– Bureau of Chemistry and Soils
– Food, Drug, and Insecticide Administration
•
1931 – Agricultural appropriations act
changed name to Food and Drug
Administration
History
• 1933-1937- several bills introduced into
the Senate to modify the Pure Food and
Drugs Act, but to no avail
• 1937 – elixir of sulfanilamide tragedy
– Sulfanilamide = limited solubility in common
solvents
– Diethylene glycol (antifreeze) proved an
excellent solvent
– Pleasing fragrance and sweet flavor – but
toxic!
– 107 died
Food, Drug and Cosmetic Act of 1938
• Required new drugs to be shown safe
before marketing (new drug application –
NDA)
• Authorized factory inspections
• Extended controls to cosmetics and
therapeutic devices
• Authorized standards for foods
• Added court injunctions to previous
penalties of seizure and prosecution
New tragedy reform
• 1961 – thalidomide, sedative-hypnotic
marketed to pregnant women to combat
morning sickness, found to cause birth
defects
• Safety concerns led FDA’s Dr. Frances
Kelsey to keep it off of U.S. market
• Distributed in U.S. only as investigational
product, though recipients not informed of
investigational status
Kefauver-Harris amendments of
1962
• Required
– Demonstration of efficacy
– Informed consent
– Control of investigational drugs
• 1963 – implemented via Investigational New
Drug (IND) regulations requiring
– Submission of protocols
– Identification of clinical investigators involved and
submission of their qualifications
– Identification of facilities involved with the studies
Judicial concurrence
• 1970 – Court of Appeals upholds
enforcement of 1962 amendments – rules
commercial success alone ≠ substantial
evidence of safety and efficacy
• 1973 – Supreme Court upholds
effectiveness law and endorses FDA
regulatory actions to control entire classes
of products rather than relying on timeconsuming litigation
Other additions
• 1971 – Bureau of Radiological Health
• 1972
– Regulation of biologics, including serums,
vaccines, and blood products transferred from
NIH
– Over-the-Counter (OTC) drug review initiated
• 1976 (and 1990) – Medical Device
regulations
•
•
•
•
•
•
•
•
•
FDA-Legal Authority
1902 – Biologics Control Act
1906 – Pure Food and Drug Act
1938 – Federal Food, Drug, and Cosmetic Act
1944 – Public Health Service Act
1951 – Food, Drug, and Cosmetics Act
Amendments
1962 – Food, Drug, and Cosmetics Act
Amendments
1966 – Fair Packaging and Labeling Act
1976 – Medical Device Regulation Act
1987 – Prescription Drug Marketing Act
•
•
•
•
•
•
•
•
•
FDA-Legal Authority
1988 – Anti–drug Abuse Act
1990 – Nutrition Labeling and Education Act
1992 – Prescription Drug User Fee Act
1994 – Dietary Supplement Health and
Education Act
1997 – Food and Drug Modernization Act
2002 – Bioterrorism Act
2002 – Medical Device User Fee and
Modernization Act (MDUFMA)
2003 – Animal Drug User Fee Act
2007 – Food and Drug Administration
Amendments Act of 2007
Product Development
Process
•
•
•
•
•
•
Phases of Product Development
CBER and CDER
Preclinical Studies
Phase I
Phase II
Phase III
Approval or Licensing
Phase IV or Post Approval Studies
Drug Development and Review Process
YEARS
1
Phase I
2
3
20 to 80
Healthy
Volunteers
Test
% of all
new drugs
that pass
Assess toxicity
and biological
activity
FILE
IND
PURPOSE
Laboratory and
Population Animal Studies
Determine
Acute
Toxicity and
Dosage
~70% of
INDs
Phase II
4
5
100 to 300
Subject Volunteers
Evaluate
effectiveness.
Look for Side
effects.
Phase III
6
7
FDA
8
Verify effectiveness,
monitor adverse
reactions from
Cumulative dosing and
delayed Toxicity
~27% of
INDs
Approval
10
1,000 to 3,000
Subject Volunteers
Expedited Review: Phases II and III combined to
shorten approval process on new medicines for serious
& life-threatening diseases.
~33% of
INDs
9
Post-marketing
safety monitoring
FILE
NDA
Preclinical
Testing
Review
usually
takes
about
½ - 1 year
~20% of
INDs
Distribution
Education
Goals of Product Development
• Safety
• Efficacy
Preclinical Studies
• Animal studies
• GLPs = Good Laboratory Practices
Pre-Approval: Phase I, II, III
• Phase I, II and III studies are conducted
prior to the approval or licensure of a
product
– Exception: post-approval for new indication
• These studies are conducted under IND or
IDE
• IND = Investigational New Drug
Application
• IDE= Investigational Device Exemption
Phase I
• First time evaluation in humans
• Generally small numbers of subjects (20
to 80)
• Determine early safety concerns
• Determine safe dose range
• Identify side effects
• Route of administration
Phase II
•
•
•
•
•
•
Larger group of subjects (hundreds)
Further evaluate safety
Evaluation of appropriate dose
Evaluate early effectiveness
Determine common side effects
Usually with comparator product
Phase III
•
•
•
•
•
•
Large group of subjects (thousands)
Confirm effectiveness
Continue to evaluate safety
Evaluate risk/benefit relationship
Provide adequate basis for labeling
Randomization
Randomization
• Subjects are assigned by chance to
receive the study product or
placebo/standard treatment
• Intervention group – those subjects
receiving the investigational product
• Control group – those subjects receiving
placebo or standard care
Blinding
• Prevents bias
• Single blind – subject does not know if
they receive investigational product or
placebo
• Double blind – neither subject or
investigator know if the subject receives
investigational product or placebo
Approval or Licensing
• NDA = New Drug Application (drugs)
• BLA = Biologics Licensing Application
(biologics)
• ANDA=Abbreviated New Drug Application
(generics)
• PMA = Pre-market approval (devices)
• NADA = New Animal Drug Application
Terminology
• Drugs and devices are approved
• Biologics are licensed
Phase IV
• Post approval or post licensure
• Safety Monitoring
– AERS = Adverse Event Reporting System
(Med Watch); CDER & CBER
– VAERS = Vaccine Adverse Event Reporting
System; CDC & CBER
• Lot Release
Drug Approval
• FDA’s determinations on drug approval depend on the
submission of reliable data from clinical trials
• Regulatory review of the data is a multidisciplinary
approach
– Clinical, pharmacology/toxicology, clinical pharmacology, drug
quality (chemistry), and statistics
• FDA’s assessment on the validity/reliability of the data is
often based on inspections at the time of marketing
application submission
– Clinical investigators
– Sponsors
– Contract Research Organizations (CROs)
Bioresearch Monitoring
How Does FDA Ensure Data
Integrity and Human Subject
Protection?
BIORESEARCH MONITORING
PROGRAM (BIMO)
BIMO Program
Comprehensive program of
on-site inspections and data
audits designed to monitor all
aspects of the conduct and
reporting of FDA-regulated
research
BIMO Program Objectives
• Protect the rights, safety, and welfare of subjects
in FDA-regulated trials
• Determine the accuracy and reliability of clinical
trial data submitted to FDA in support of
research or marketing applications; and
• Assess compliance with FDA’s regulations
governing the conduct of clinical trials, including
those for informed consent and ethical review
BIMO Inspections
• Each FDA Center has oversight of inspections of research related
to the product(s) it regulates
• Inspections are usually conducted by ORA field investigators
– Field inspectors are NOT specifically assigned to CDER
– All Field inspectors are responsible for conducting inspections
for all centers (CBER, CDER, CDRH, CFSAN, etc.)
BIMO Inspections Completed FY09
Center
CI
IRB
Spon/Mon
GLP
Total
CBER
83
15
11
6
115
CDER*
458
102
73
36
674
CDRH
163
79
59
4
305
CFSAN
0
0
0
1
1
CVM
26
na
4
15
45
All Centers
730
196
147
53
1135
FDA/CDER GCP Regulations
Scope
FDA has regulations governing the
approval, conduct, review and reporting
of clinical research (and non-clinical)
intended for submission
Regulatory oversight
Institutional Review Boards (IRBs),
Sponsors, CROs/Monitors, Clinical
Investigators
Relevant Regulations 21 CFR
include (but not limited •Part 50: Protection of Human Subjects
to)
•Part 54: Financial Disclosure
•Part 56: Institutional Review Boards
(IRB)
•Part 312: Investigational New Drugs
(IND)
•Part 314: New Drug Applications (NDA)
These are legally enforceable requirements
Clinical Investigators
• Compliance Program
– Inspections of CIs (physicians, researchers)
conducting clinical trials on drug and biologic
products
• Inspection
– Usually preannounced
– Inspection includes
• an interview with the clinical investigator and
pertinent study staff
• an in-depth study/data audit – to validate study
findings and verify compliance with regulations
FDA Expectations of Clinical
Investigators
• Adherence to Code of Federal Regulations
– Knowledge of Clinical Investigator regulations
– Understanding Clinical Investigator
responsibilities
General Clinical Investigator
Responsibilities
• Ensuring that an investigation is conducted
according to the
– Signed investigator statement (Form 1572)
– Investigational plan
– Applicable regulations
• Control of drugs under investigation
• Adequate Recordkeeping
• Ensuring that informed consent is adequately
obtained according to 21 CFR 50
• Ensuring IRB review, approval and reporting
requirements are met IAW 21 CFR 56
Most Common CI Deficiencies
•
•
•
•
Failure to follow the investigational plan
Protocol deviations
Inadequate recordkeeping
Inadequate accountability for the
investigational product
• Inadequate subject protection – including
informed consent issues
Administrative/regulatory options
• Untitled or Warning letter
• Initiation of disqualification procedures
• Sharing information with Office of Criminal
Investigations (OCI) for pursuit of
prosecution
• Recommendation for rejection of site/study
data
Institutional Review Boards (IRBs)
• Board, committee, or other group formally
designated by an institution to
– review
– approve the initiation of
– conduct periodic review of
biomedical research involving human subjects
• Primary purpose of IRB oversight
– ensure protection of rights, safety, and welfare
of the human subjects
IRB Inspections
• Compliance program
– provides for regularly scheduled inspections to verify
compliance with regulations
– Objective is protection of human subjects rather than
data validation
• Inspections
– usually preannounced
– consist of
• interviews with responsible IRB staff
• in-depth review of SOPs, files, and records
• review of active studies to assess IRB operations
Most common IRB deficiencies
•
•
•
•
Inadequate initial and/or continuing review
Inadequate SOPs
Inadequate membership rosters
Inadequate meeting minutes
Specific to devices – lack of or incorrect
SR/NSR determination
Administrative/regulatory options
• Untitled or Warning letter
• Restriction of functions
– prohibiting increase of subject population in
on-going FDA-regulated studies
– prohibiting review of new FDA-regulated
studies
• Initiation of disqualification procedures
Sponsors/CROs/Monitors
• Compliance program
– covers parties responsible for initiating and
overseeing research and for submitting research
results to FDA
– lists sponsor responsibilities
• Inspections
– usually preannounced
– consist of interviews and audits of study records
– objective is to both evaluate compliance with
regulations and validate data
– commonly assigned for NDAs for new molecular
entities (NMEs) and for PMAs
Most common S/M deficiencies
• Inadequate monitoring
• Failure to bring investigators into
compliance
• Inadequate accountability for the
investigational product
Administrative/regulatory options
• Untitled or Warning letter
• Invocation of the Application Integrity
Policy (AIP)
• Refusal to accept site or study data
• Denial of NDA/BLA/PMA
• Sharing information with Office of Criminal
Investigations (OCI) for pursuit of
prosecution
• DSI Homepage: www.fda.gov/cder/offices/dsi
Includes links to the Clinical Investigator Inspection List
(NEW), Bioresearch Monitoring Information Systems
(BMIS) files (NEW), Warning Letters, NIDPOE Letters,
Lists of Disqualified or Restricted or Debarred
Investigators, Code of Federal Regulations, etc.
• FDA Homepage: www.fda.gov
Includes links to the Federal Register Notices, FDA
guidance documents.
• Compliance Programs:
www.fda.gov/ora/compliance_ref/default.htm