Transcript Clinical Trial Quality and Compliance: An FDA Perspective

The IND Process
David A. Lepay, M.D., Ph.D.
Senior Advisor for Clinical Science
Office of the Commissioner, US FDA
Johns Hopkins Program
December 10, 2001
FDA’s Mission
FDA has a broad public protection mission
Ensure the safe use of regulated products
that are themselves safe and efficacious
Underlying this mission is FDA decisionmaking on product applications and labeling
Based on complete and accurate information from
well-designed, ethically-conducted, and wellmonitored clinical research
FDA’s Mission in Clinical
Research
Ensure Implementation of Good Clinical
Practice Standards
Embodied in FDA regulation and guidance
since the 1960’s and ‘70’s
International Standard (ICH E6) since 1996
Enforced through FDA’s review process and
in its program of on-site inspections
U.S. Clinical Investigator inspections from 1962
Ethics Committee (IRB) inspections from 1978
International CI inspections from 1980
GCP is Comprehensive
International ethical and scientific quality
standard for designing, conducting,
recording, and reporting trials that involve
the participation of human subjects
GCP embraces trial objectives, trial design,
study oversight, data collection and quality
assurance, study analysis, as well as human
subject protection in studies that support
product applications
Good Clinical Practice
GCP is most fundamentally a System of
Shared Responsibilities
Clinical Investigators
Institutions/Institutional Review Boards
Industry (Sponsors/Monitors)
Government Regulators
FDA’s Authority to Regulate
Federal Food Drug and Cosmetic Act
Requires that an FDA approved
marketing or research permit be
obtained before certain commodities
(such as human drugs, medical devices,
veterinary drugs, food additives, etc.)
may move across state lines
Pharmaceuticals may move
across state lines during two
stages of human use
Research prior to “approval”
Requires research permit: e.g,
Investigational New Drug Exemption (IND)
Marketing after “approval”
Requires marketing permit: e.g., New Drug
Application (NDA)
What is an IND/IDE ?
An exemption from the law which
otherwise requires that a drug (biologic,
device) be approved before it can be
transported across state lines
The standard for approval is evidence of
safety and efficacy
The IND exemption is granted for purposes
of clinical investigation (research)
Importance of the IND
Affirms a body of knowledge about the
manufacturing, pharmacology, and
toxicology of the drug to support its use in
human testing
Requires that the clinical investigation(s) be
performed in accordance with Good Clinical
Practice (GCP)
Provides an additional level of protection
through FDA oversight
The FD&C Act Defines
“Drug” Very Broadly
Any of:
Article recognized in the U.S. Pharmacopeia,
official Homeopathic Pharmacopeia of the US,
or official National Formulary, or any
supplement
Article intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of
disease in man or other animals
The FD&C Act Defines
“Drug” Very Broadly
Any of:
Article (other than food) intended to
affect the structure or any function of
the body of man or other animals
Article intended for use as a component of
any article specified in clauses above
Section 201(g) of the FD&C Act
“Clinical Investigation” is
also Defined Broadly
Any experiment in which a drug is
administered or dispensed to, or used
involving, one or more human subjects.
For the purposes of this part, an
experiment is any use of a drug except
for the use of a marketed drug in the
course of medical practice
21 CFR 312.3
So When Is an IND
Required ?
In general: An IND is required when
an unapproved drug (or biologic) is
used in a clinical investigation
What About Approved
Products
No IND is needed when an approved
product is used in the course of medical
practice (even for an indication different
from the approved indication)
But an IND may be required when an
approved products is used in a clinical
investigation
What About Approved
Products
An IND is needed if:
The clinical investigation is intended to be
reported to FDA as a well-controlled study
in support of a new indication or a
significant change in the labeling of the
drug
The clinical investigation is intended to
support a significant change in advertising
for the product
What About Approved
Products
With the above caveats, clinical
investigation of an approved product may
be exempt from IND requirements if:
The investigation does not involve a route of
administration or dosage level or use in a
patient population or other factor that
significantly increases risks AND
The investigation is conducted in accordance
with IRB and informed consent requirements
What About Approved
Products
FDA has generally allowed the IRB to
assess whether risk of an approved
product is increased for a given protocol
But FDA retains final authority for such
determinations
What About Approved
Products
It is also important to note that shelf
chemicals which bear the same “name”
as an approved product are not
considered as “lawfully marketed”
equivalents of the approved product
Approval is specific to dose, formulation,
and applicant
Need for an IND/IDE:
Who to Contact with Questions
Drugs (CDER)
Drug Information Branch: (301) 827-4573
Biological Products (CBER)
(301) 827-0373
Medical Devices (CDRH)
IDE Staff: (301) 594-1190
Food Safety (CFSAN): (202) 418-3126
Related Information
GCP Regulations
IND/IDE Regulations: 21 CFR Part 312/812
IRB Regulations: 21 CFR Part 56
Informed Consent Regs: 21 CFR Part 50
All are accessible at:
www.fda.gov/oc/gcp
Related Information
IND Forms
Available on-line through:
www.fda.gov/cder/regulatory/applications/
IND: What is Required -1General Investigation Plan
Investigator’s Brochure
Protocol(s): Later protocols submitted as
amendments
Chemistry, manufacturing and control
information
Animal pharmacology and toxicology
information
IND: What is Required -2Previous human experience
Additional information
Dependence and abuse potential
Plans for pediatric studies
Amount of information required in each
section depends on novelty of the drug,
extent studied, and known or suspected
safety concerns
The FDA Form “1572”
IND sponsors are required to obtain a signed
FDA Form “1572” from each clinical
investigator, containing:
Name and address of CI
Name and code number of any protocol(s)
Name and address of research facility and
any clinical labs
Name and address of responsible IRB
Names of subinvestigators
Signed commitment by the investigator
Clinical Investigator
Responsibilities*
Personally conduct or supervise
investigations
Ensure all persons assisting in conduct of
studies are informed of their obligations
Ensure informed consent (21 CFR 50) and
IRB review, approval , and reporting (21
CFR 56) requirements are met
*(Form FDA 1572: #9. Commitments)
Clinical Investigator
Responsibilities*
Conduct studies according to relevant,
current protocol
Make changes in a protocol only after
notifying the sponsor
Maintain adequate and accurate records
Make records available for inspection
Agree to comply with all other
requirements in 21 CFR 312
*(Form FDA 1572: #9. Commitments)
Review of IND Application
FDA also has responsibilities under GCP
The focus of FDA’s IND Review is on
safety for human research subjects and
ensuring that the studies will produce
useful information to assess safety and
efficacy of the test product
Reviews are Conducted by
Teams of Specialists
Medical Officer
Consumer Safety Officer/Project Manager
Statistician
Chemist
Pharmacologist
Human Biopharmaceutics
(Microbiologist)
Review of IND Application
Review team has 30 days to review
Focus of review is always on safety/
human subject protection
No News = Good News
IND Application: If Problems..
“Clinical Hold”
Legal order to delay or stop the study in the
U.S.
Subjects may not be given the investigational
drug
May be imposed if:
Exposure of subjects to unreasonable risk
(includes manufacturing problems)
Investigator brochure is misleading, erroneous,
or materially incomplete
Investigator is not qualified
Drug Development Under an IND
Review Team Monitors
New Protocols (IND amendments)
Safety reports
Annual reports
Additional chemistry, animal toxicology,
microbiology data
Review team is available to consult/meet
with sponsors: advise on protocol design,
advise on drug development plan
IND and Non-US Studies
Studies performed outside of the U.S.
may be conducted with or without IND
With an IND:
Test article can be exported from the U.S.
Study must conform to U.S. IND
regulations (including U.S. IRB and
informed consent rules)
IND and Non-US Studies
Studies performed outside of the U.S.
may be conducted with or without IND
Without an IND
May be acceptable for FDA review in
support of a marketing application
Export of the test article from the U.S.
must conform to FDA regulations
Export of an Investigational
Drug
Mechanisms (21 CFR 312.110)
FDA authorization of a written request
from the person that seeks to export
Adequate information; investigational
purposes only; can be legally used in the
importing country for investigation; specifies
quantity/frequency of shipment
FDA authorization of a formal request
from the government of the receiving
country
Export of an Investigational
Drug
1996 law also allows drug export for
investigational use without prior FDA
approval if intended for use in one of 25
countries
Australia; Canada; Israel; Japan, New
Zealand; Switzerland; European Union
Member States (15), Iceland, Norway,
and Liechtenstein
IND Content/Submission:
Who to Contact with Questions
Center for Drugs
ODE I
Cardio-Renal (110)
301-594-5300
Neuropharm (120)
301-594-2850
Oncology (150)
301-594-2473
Center for Drugs
ODE II
Anesthetic, Critical
Care & Addiction (170)
301-827-7410
Metabolic/Endocrine
(510)
301-827-6430
Pulmonary (570)
301-827-1050
IND Content/Submission:
Who to Contact with Questions
Center for Drugs
ODE III
Medical Imaging &
Radiopharm (160)
301-827-7510
GI & Coagulation
(180)
301-827-7310
Repro/Urologic (580)
301-827-4260
Center for Drugs
ODE IV
Anti-Infective (520)
301-827-2120
Antiviral (530)
301-827-2330
Special Pathogens &
Immunologic (590)
301-827-2336
IND Content/Submission:
Who to Contact with Questions
Center for Drugs
ODE V
Derm/Dental (540)
301-827-2021
Anti-Inflammatory,
Analgesic &
Ophthalmic (550)
301-827-2040
Over-the-Counter
(OTC) (560)
301-827-2222
IND Content/Submission:
Who to Contact with Questions
Center for Biologics (CBER)
Office of Vaccines Research and Review
(301) 827-0654
Office of Blood Research and Review
(301) 827-3524
Office of Therapeutics Research and Review
(301) 827-5099
Office of Generic Drugs
Who to Contact with Questions
OGD Regulatory Support Branch
(301) 827-5862
IDE Content/Submission:
Who to Contact with Questions
Center for Devices and Radiological
Health (CDRH)
General, Restorative, and Neurological
Devices: (301) 594-1184
Clinical Laboratory Devices: (301) 5943084
Cardiovascular and Respiratory
Devices: (301) 443-8320
IDE Content/Submission:
Who to Contact with Questions
Center for Devices and Radiological
Health (CDRH)
Ophthalmic and ENT Devices: (301)
594-2205
Reproductive, Abdominal, and
Radiological Devices: (301) 594-5072
Dental, Infection Control, and General
Hospital Devices: (301) 443-8879
Sponsor Responsibilities
Selecting Qualified Investigators
Providing investigators with information they need to
conduct an investigation properly.
Ensuring proper monitoring of the investigation(s)
Conduct per protocol
Ethical considerations
Control of investigational product(s)
Safety reporting
Sponsor Responsibilities
Review Ongoing Investigations
A sponsor who discovers that an investigator is
not complying with the signed 1572, general
investigation plan, or regulations shall promptly
either:
secure compliance or
end the investigator’s participation in the
investigation (discontinue shipment and
require return/disposal of drug; notify FDA).
Sponsor-Investigators
FDA regulations allow an individual to be
both study sponsor and clinical
investigator
The Dilemma:
Many sponsor-investigators believe that the
lack of external monitoring and oversight
means that they can perform to a lower
standard
Sponsor-Investigators
The Dilemma -2Where a sponsor and an investigator are the
same, the number of GCP control points is
reduced from four to three
A sponsor-investigator therefore needs to be
more (not less) informed of responsibilities
and more attentive to standards of study
conduct and subject protection
Subject Education
Subject Education is an often neglected
facet of GCP; yet, an educated, fully
informed, and inquiring subject may be
the best resource for ensuring ethical and
quality performance in a clinical trial
The IRB and institution should pay
particular attention to informing subjects
where to go with questions or complaints
Reporting to FDA
Sponsors are required to report serious
non-compliance
But anyone can report complaints in FDAregulated clinical trials to FDA
FDA’s GCP website (www.fda.gov/oc/gcp)
highlights where to report complaints in
clinical trials
New At FDA
FDA has recently established a new
Office for Good Clinical Practice to
coordinate GCP across FDA and
beyond...
OGCP: Structure
Small Office
Strategically located
Office of the Commissioner and its Office of
Science Coordination and Communication
Key Positions
David A. Lepay, MD PhD: Senior Advisor for Clinical
Science and Director
Stan W. Woollen: Associate Director for Bioresearch
Monitoring
Bonnie Lee: Associate Director for Human Subject
Protection Policy
OGCP: Functions
Centralized (Commissioner’s Office)
Role in:
GCP Policy
Bioresearch Monitoring of Clinical Trials
GCP Initiatives
International GCP (harmonization)
activities
GCP Education and Outreach
OGCP and Quality
Assurance
OGCP will reflect FDA’s Commitment to
Quality Assurance
Internally
Coordinating QA for the Agency’s clinical
Bioresearch Monitoring Program of on-site
inspections
Externally
Coordinating Agency GCP policy and
initiatives to enhance the quality of clinical
research
Clinical Trial QA:
What We Should Strive For
Building quality in upfront
Assuring quality throughout
Developing capacity for continuous
quality improvement now and in the
future
Working Together:
Plentiful Opportunities
Well-designed, well-conducted clinical
trials are not easy
If you don’t want to “do it right”, you
should not be conducting clinical trials
The best systems can only emerge
from the broadest possible
participation
Working Together:
Plentiful Opportunities
Quality assurance and quality
improvement are integral to
development of the best systems !