Transcript Slide 1

Clinical Research and Regulations
Marilyn Marshall QAO Office of the Vice President of Research
International Conference on Harmonization
E6: Good Clinical Practice: Consolidated
Guideline
FDA’s Role in Clinical Research
• A new drug cannot be marketed in
the United States until there is
“substantial evidence” as to its
safety and effectiveness
FDA’s Role in Clinical Research
• Regulation 21 CFR 314.126:
“substantial evidence” is collected in
“adequate and well-controlled trials”
Characteristics of Adequate and
Well-controlled Clinical Trials
• Protocol contains a clear statement of
objects of the study
• Study design permits a valid
comparison with a control to provide a
quantitative assessment of the drug
effect
• Methods of assessment of subjects’
responses [efficacy and safety] are
well-defined and reliable
Characteristics of Adequate and Wellcontrolled Clinical Trials
• Study report provides sufficient details of
study design, conduct and analysis
• Patients were assigned to treatment and
control groups in a way that minimizes bias
[e.g., randomization]
• Adequate measures were used to minimize
bias of subjects, observers, and data analysts
[e.g., blinding]
FDA’s Role in Clinical Research
Reports of adequate and well-controlled
investigations provide the primary
basis for determining whether there is
“substantial evidence” to support the
claims of effectiveness for new drugs
and antibiotics.
21 CFR 314.126
FDA’s Role in Clinical Research
The purpose of conducting clinical
investigations of a drug is to
distinguish the effect of a drug from
other influences such as …
• Spontaneous change in the course of
the disease
• Placebo effect
• Biased observation
21 CRF 314.126
Phases of Clinical Research:
• Phase 0: Exploratory
• Phase I: Pharmacokinetics and safety in
humans
• Phase II: Dose finding and efficacy
• Phase III: Pivotal studies
• Phase IV: Post approval commitments
21 CFR Part 11 (overview)
Electronic Records, Electronic
Signatures
 21 CFR Part 11
March of 2003 the FDA withdrew the
Guidance document on Part 11. However,
this does not mean that we you should
ignore the regulation.
21 CFR Part 11
(cont.)
 Part 11 applies to Any Records that you
choose to created, modified, maintained,
archived, retrieved or transmitted in
electronic form.
21 CRF Part 11 Key
Requirements
 Validation
 Audit Trails
 Security
 Record retention and protection
Electronic Systems Requirements
• 21CFR Part 11
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Security
Data Integrity
Data Access
User Authentication
Audit Trail
• HIPPA
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Security
Data Integrity
Data Access
User Authentication
Audit Control
Transmission
(Encryption)
21 CFR 50. 20 (overview)
General Requirements for Informed
Consent
– …no investigator may involve a human
being as a subject in research…unless the
investigator has obtained the legally
effective informed consent of the subject
or the subject’s legally authorized
representative.
– The information…shall be in a language
understandable to the subject or the
representative.
21 CFR 50. 20 (cont.)
General Requirements for Informed
Consent
– No informed consent,… may include any
exculpatory language… which the subject
or the representative is to waive or appear
to waive any of the subject’s legal rights,
– or release or appear to release the
investigator, the sponsor, the institution,
or its agents from liability for negligence.
21 CFR 56.109 (overview)
IRB Review of Research
 An IRB shall:
– review and have the authority to approve,
require modifications in…or disapprove all
research activities covered by these
regulations…notify investigators and the
institution in writing of its decision to
approve or disapprove…
– require that information given to the
subjects as part of the informed consent is
in accordance with §50.25.
– conduct continuing review of research…
21 CFR 312.56 (overview)
Review of Ongoing Investigations
The sponsor shall monitor the progress of all
ongoing investigations being conducted
under its IND. A sponsor who discovers that
an investigator is not complying with the
signed agreement (Form FDA-1572), …shall
either secure compliance, or discontinue
shipments of the investigational new
drug…and shall notify the FDA.
21 CFR 312.60 (overview)
General Responsibilities of
Investigators
 An investigator is responsible for:
– ensuring that investigation is conducted
according to the signed investigator
statement…
– protecting the rights, safety, and welfare of
the subjects…
– Obtain the informed consent of each
human subject…
– control of drugs under investigation
ICH 5.1 (overview)
 ICH 5.1 Quality Assurance and Quality
Control
– 5.1.1 The sponsor is responsible for
implementing and maintaining quality
assurance and quality control systems
with written SOPs to ensure that trials are
conducted and data are generated,
documented (recorded), and reported in
compliance with the protocol, GCP, and
the applicable regulatory requirement(s).
Investigator-Initiated Clinical
Research
• Form 1571
• Sponsor is the individual investigator and
therefore assumes all responsibilities of both
Sponsor an Investigator
Sponsor-Investigator
Obligations
SI is obligated to monitor the clinical study
• SI is responsible to IRB
• SI is required to keep accurate and complete
records of study
Purpose of Clinical Study Monitoring
• Protect the interests of subjects involved in
the clinical research
• Protect the interests of the sponsor or
academic institution
• Adhere to federal and international
requirements
Role of the Monitor
1. Verify subjects have been properly
consented prior to any study related
procedure
2. Verify eligible subjects are entered in
the study and no eligible subjects
excluded
3. Verify protocol is being followed as
written
Role of the Monitor
4. Verify that adverse events are being
recorded and reported to Sponsor in
timely manner
5. Verify that violations and deviations are
recorded and deviations are preapproved where possible
6. Verify that the data are accurately and
consistently recorder in CRF’s
Role of the Monitor
7. Verify that CRF data are supported by
source documents
8. Verify that Principle Investigator is
actively overseeing the conduct of the
clinical study
9. Verify that all IRB approvals are in
place before changes are implemented
Role of the Monitor
10.Verify that Regulatory binder is being
maintained
11. Verify that drug study medication is
returned as required and accounted for
12. Verify that only authorized study
personnel are involved in conduct of
study
Role of the Monitor
14. Verify that study is being conducted
honestly and with no fraud
15. Ensure data will withstand FDA and
other regulatory scrutiny for
completeness and accuracy
Terms
Case Report Form [CRF]
A printed, optical or electronic
document designed to record all
protocol-required information to be
reported to the sponsor on each trial
subject
Terms
Adverse Event [AE]
Any untoward medical occurrence in a
patient or clinical investigational
subject administered an investigational
drug and which does not necessarily
have a causal relationship with the
treatment/usage.
Adverse Event [AE]
• Any unfavorable and unintended sign,
including an abnormal laboratory findings
• Symptom or disease temporally
associated with the use of an
investigational drug
Describing an Adverse Event
• Adverse events should be described in
terms of a change in the status of a
subject’s health, NOT in the action taken
or outcome
Serious Adverse Event (SAE)
• Event that results in any one of the
following…
• Death
• Life threatening
• Inpatient hospitalization
• Persistent/significant disability/incapacity
• Leads to any congenital anomaly/birth defect
Adverse Event Reporting
Investigators must report
• All AEs [routine and serious] in the CRF
• SAEs to both the sponsor and IRB
immediately
• 7-calendar day notification if SAE is death
or life threatening…followed by a 15 day
written report.
Source Documents:
• Original documents, data, and records
[e.g., hospital records, clinical and
office charts, laboratory notes, memo’s,
subjects’ diaries or evaluation
checklists, pharmacy dispensing
records, recorded data from automated
machines….]
Tools to Perform Audits
Logs and Checklists
Tools to Perform Audits
Log for Informed Consent Verification
Informed Consent Log
HSC:
Principal Investigator:
Title of Protocol No.:
Reviewer
Date
Subject ID
Consent
Form
Version
Date
IRB
Approva
l Date
Date
Subject
Signed
Surgery
Date
Date PI
Signed
HIPAA
Subject
Signed
Comments
Informed Consent Log
HSC:
Principal Investigator:
Title of Protocol No.:
Reviewer
Date
Subject ID
Consent
Form
Version
Date
IRB
Approva
l Date
Date
Subject
Signed
Surgery
Date
Date PI
Signed
HIPAA
Subject
Signed
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Comments
Materials and Equipment:
HSPP Location
Project Approval Form Packet as approved by the IRB:
IRB Approval Letter
Date of approval________
Informed consent as approved by the IRB
Approval dates checklists
HIPAA Authorization Form as approved by the IRB
Approval dates _____________
Amendment Checklists
Site Authorization Form
Protocol Revision Checklists
Brochure Revision Checklists
Periodic Review Form
Adverse Events documentation
Copy of Verification Of Training Forms and log in checklist dates of
all VOTF changes
Investigators’ Location
Investigator’s File for clinical study and Patient Binders
Review Study SOPs/Protocol
Review Patient Informed consent/HIPPA and report on Consent
Log Form
Review Inclusion/Exclusion Signature pages and report on Patient
I/E Form
Review Case Review Forms for protocol compliance
Review payments to patients per protocol/approved by IRB
Review training records of personnel
Review Regulatory Documents
Review Drug or Device Accountability and Handing
Other terms and conditions of IRB approval
Site Regulatory Binder
Section 1: Protocols and Amendments
Section 2: FDA Form 1572
Section 3: IRB Information and Approvals
Section 4: Informed Consent & HIPAA
Section 5: Personnel CV’s & Licensure
Section 6: Investigator Brochure
Section 7: SAEs and IND Safety Reports
Section 8: Patient Screening & Enrollement
Site Regulatory Binder
Section 9: Drug Accountability
Section 10: Laboratory Information
Section 11: Pharmacy Information
Section 12: Monitoring Information
Section 13: Site Signature Log
Section 14: Case Report Forms
Section 15: Correspondence
Section 16: Other
Summary of GCP Requirements
 Written Procedures
SOPs, Protocol
 Oversight
IRB, Regulatory Agencies, Sponsor
Informed Consent Form (ICF)
Subjects/ Patients
Summary of GCP Requirements
(cont.)
 Qualification/ Training
- Investigator, Nurses, Monitors, CRO, Lab,
Auditors, etc
 Documentation
- Source, CRF, ICF, IDB,
Summary of GCP Requirements
(cont.)
 Sponsor responsible for implementing and
maintaining quality systems
 Must be covered by written SOPs
 Must assure adherence to the
protocol/SOPs/GCP/regulations
 Audit itself must be separate from routine
monitoring and QC functions
 Must report any sites that are prematurely
terminated from the study (ICH 5.21, CFR
312.56)
Summary of GCP Requirements
(cont.)
Auditors must be:
– Independent of clinical trial/data collection
– Qualified by training and experience
– Qualifications must be documented
FDA Findings
Violations related to informed consent (21 CFR
50.25, 21 CFR 50.20, 21 CFR 312.60)
You failed to obtain proper informed consent in
that the following essential elements of informed
consent were not included in the consent form
that was provided to the healthy volunteers.
The consent form failed to disclose that the
inhalation of XX was an experimental use of the
drug.
FDA Findings
Failure to inform the IRB of changes to
the protocol [21 CFR 312.66].
You failed to inform and obtain approval from [X]
Institutional Review Board [X] for the changes in
the protocols;…
FDA Findings
Failure to conduct and investigation in
accordance with the investigational plan 21
CFR Part 812.110(b)).
You failed to enroll subjects according to the
inclusion/exclusion criteria.
You also failed to perform all required tests at study
visits. Your records contained instances where study
procedures, including laboratory testing, were either not
performed or were not consistently followed at scheduled
examinations.
FDA Findings
Your firm failed to ship investigational new
drugs only to investigators participating in
the investigation. [21 CFR 312.53(b)]
In May 2001, your firm shipped the wrong
investigational vaccine to a clinical investigator
who was not conducting a study for that test
article. While the vial labels identified the test
article that was shipped, it was not the test
article that was intended for use with the type of
cancer in the investigator’s protocol.
Fenster Warning Letter
Public Health Service
Food and Drug Administration 9200 Corporate Boulevard
Rockville, Maryland 2085
March 21, 2006
WARNING LETTER
VIA FEDERAL EXPRESS
Paul Fenster, M.D.
Associate Professor of Medicine
University of Arizona
1501 North Campbell Ave.
P.O. Box 245037
Tucson, AZ 85724-5037
Dear Dr. Fenster:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug
Administration (FDA) inspection conducted at your clinical site from October 3, 2005, through November 22,
2005, by an investigator from the FDA Los Angeles District Office. The purpose of this inspection was to
determine whether activities and procedures related to your participation in the clinical study for the
[redacted] , that ultimately resulted in approval under PMA [redacted] complied with applicable federal
regulations. The [redacted] is a device as that term is defined in section 201(h) of the Federal Food, Drug, and
Cosmetic Act (the Act), 21 U.S.C. 321(h). This letter also requests prompt corrective action to address the
violations cited and discusses your written responses to the noted violations.
FDA Findings
Failure to ensure that the investigation is conducted
in accordance with the signed agreement with
sponsor, the investigational plan, applicable FDA
Regulations for protecting rights, safety and welfare
of subjects under the investigator’s care and for
control of devices under investigation, and any
conditions of approval imposed by the FDA or IRB.
[21 CFR812.100 and 21 CRF 812.114(b).
In addition, you failed to supervise device use. An
investigator shall permit an investigational device to
be sued only with subjects under the investigator’s
supervision. [21CRF 812.110©].
Inspection Classifications
NAI-No Action indicated. Minor or no
objectionable practices
VAI-Voluntary Action Indicated. Some
objectionable conditions, but not serious
enough for FDA to take action
OAI-Official Action Indicated. FDA
further action recommended.
Fraud in Clinical Studies
Check for non-existent subjects and altered
or fabricated data, personnel is as stated in
the protocol
If fraud is confirmed, FDA must be notified