Transcript No Slide Title

Medical Alley
Advanced Monitoring
Workshop
Paul Below
P. Below Consulting, Inc.
October 19, 2005
Disclosure
• The presenter does not have a
significant equity interest in any of the
companies/products referenced here
• The presenter has a consulting
relationship with the following:
• GlaxoSmithKline
• Boehringer Ingelheim Pharmaceuticals
• Southeast Louisiana Chapter ACRP
This presentation and related references
are posted on my website at:
www.pbelow-consulting.com/
monitoring.html
Objectives
• The role of monitoring in Good Clinical
Practices (GCPs)
• Activities involved in on-site visits
• Common site problems and findings
• Addressing non-compliance
• Fraud and misconduct
• Electronic records
Objectives
• Interactive case studies of real-life
monitoring situations
The Role of
Monitoring in Good
Clinical Practices
Why Do We Monitor?
• Required to by regulation
• Ensure the acceptance of trial data
by regulatory authorities (i.e., FDA)
Why Do We Monitor?
• Verify that rights and well-being of
human subjects are protected
• Verify that reported data are
accurate, complete and verifiable
• Verify trial is conducted in
compliance with protocol, GCP and
applicable regulatory requirements
Good Clinical Practice
• “A unified standard for designing,
conducting, recording, and reporting
trials that involve the participation of
human subjects”
• Federal regulations (Title 21 CFR)
• Other federal regulations & state laws
• FDA “guidance documents”
GCP Regulations
• Protection of human subjects - informed consent
(part 50)
• Institutional review boards (part 56)
• Financial disclosure (part 54)
• Electronics records and signatures (part 11)
• Investigational new drugs (part 312) and
application to market a new drug (part 314)
• Investigational device exemptions (part 812) &
premarket approval of medical devices (part 814)
Other Federal Regulations
• Nuclear Regulatory Commission
regulations (10 CFR 35) for the medical
use of radioactive substances
• Department of Transportation regulations
for the shipment of infectious materials
(49 CFR)
• HIPAA Privacy Rule (45 CFR 160-164) for
the use and disclosure of protected health
information
State Laws
• Many states have laws that impact
clinical research in the following areas:
– Age of consent
– Legally authorized representative
– Clinical research registration
– Medical records privacy
– Gene research
– STD/HIV reporting
GCP Guidance Documents
• FDA Information Sheets
(www.fda.gov/oc/ohrt/irbs/default.htm)
• Guideline for the Monitoring Clinical
Investigations (January 1988)
• ICH Guidelines for Good Clinical
Practice (Published in Federal Register
- May 9, 1997)
FDA Guidance
• Represents the agency’s “current
thinking” on how to comply with the
regulations
• Not legally binding
• Non-compliance should not be cited
in a FDA Form 483
• An alternative approach can be used
if acceptable to FDA
What is ICH?
• International Conference on the
Harmonization of Technical
Requirements for Registration of
Pharmaceuticals for Human Use
• Comprised of representatives from
the U.S., European Union and Japan
• Establish guidelines to promote
mutual acceptance of data
Monitoring Requirement
• “Sponsors are responsible for …
ensuring proper monitoring of the
investigation” (812.40 and 312.50)
• “The sponsor shall monitor the
progress of all investigations
involving an exception to informed
consent” (812.47 and 312.54)
Monitoring Plan
• For significant risk device and
treatment use trials, FDA requires
written procedures for monitoring in
the investigational plan (812.25,
812.40)
• FDA can withhold or pull approval of
an application if the monitoring plan
is inadequate (812.30)
Monitoring Plan (cont)
• Monitoring plan based on:
– Trial objectives, design, endpoints
– Trial complexity
– Number/location of investigators
– Type of investigational product
– Disease under study
Type of Monitoring
• “Personal contact” should be
maintained with the investigator
throughout the trial
• Need for on-site visits before, during
and after the trial
• In exceptional circumstances, central
monitoring can be used
Selection of Monitors
• “A sponsor shall select monitors
qualified by training and experience”
(812.43)
• A list of names and addresses of all
monitors is included with the
investigational plan (812.25)
• Monitoring functions can be
transferred to a CRO (312.52)
Monitor Selection
• Need not be qualified to diagnose or
treat disease under study
• Thoroughly familiar with test article,
protocol and informed consent,
sponsor’s SOPs, and GCPs and FDA
regulations
• Qualifications should be documented
Recent FDA Warning Letter
“Study monitors were not qualified by
training and experience. Neither of the
two individuals who conducted
monitoring visits for the [redacted] study
had previous experience in clinical
monitoring; one of the two monitors had
no training in clinical trials prior to
conducting independent monitoring
trials.”
CDRH Warning Letter to Celsion Corporation (May 7, 2004)
Outstanding Monitor Traits
• Quick scientific learners
• Independent problem solvers
• Can hack the travel
• Can see the forest and the trees
• Regulatory experts
• Technologically proficient
Activities Involved
in On-Site Visits
On-Site Visit Types
• Pre-Investigation
• Periodic Monitoring
• Close-Out
Selection of Investigators
• “A sponsor shall select investigators
qualified by training and experience
to investigate the device” (812.43)
Investigator Selection
• Preliminary phone contacts and on-site
visit to determine if the investigator:
– Understands and accepts trial obligations
– Understands and accepts regulatory obligations
– Can demonstrate potential for recruitment based
on retrospective data
– Has adequate facilities
– Has sufficient time
– Has adequate number of qualified staff for
duration of trial
Investigator Selection
• Other Considerations:
– Past company performance
– Past performance with other sponsors
– References from colleagues
– Publication record
– Key opinion leaders
– FDA Debarment and Disqualified Lists
– FDA Warning Letters
– CDER Clinical Investigator Inspection List
FDA Investigator Lists
• Debarment List:
– Convicted of a felony under Federal law for conduct
relating to development or approval of any drug
product
– www.fda.gov/ora/compliance_ref/debar/default
• Disqualified/Restricted/Assurances Lists:
– Disqualified through hearing process or restricted
through consent agreement
– www.fda.gov/ora/compliance_ref/bimo/
dis_res_assur.htm
FDA Investigator Lists
• Clinical Investigators Inspection List:
– Contains information gathered from inspections of
clinical investigators who have performed studies
with investigational human drugs
– The inspections were conducted as part of FDA’s
Bioresearch Monitoring Program
– www.fda.gov/cder/regulatory/investigators/
default.htm
Pre-Investigation Visit
• Location
– All facilities where trial conduct will occur
• Materials
– Investigator’s Manual
– Device
– Agenda
Pre-Investigation Visit
• Participants
– Principal Investigator/Co-Investigators
– Study coordinator/research nurse
– Other medical staff (technicians)
Pre-Investigation Activities
• Discussion of device background,
protocol procedures
• Discussion of resources
– Staff availability and training
– Adequate time and workload
– Interest and motivation level
– Available patients (review retrospective data)
– Competing trials
Pre-Investigation Activities
• Review case report forms and
required source documentation
• Discussion of regulatory obligations
– IRB review
– Informed consent
– Record keeping
– Investigational product
– Company policies and procedures
Pre-Investigation Activities
• Tour facilities
– Patient evaluation and treatment facilities
– Emergency facilities and staff
– Laboratory
– Device storage and security
– Files storage (administrative and patient)
• Collect investigator documentation
Investigator Documentation
• CV and/or statement of relevant
experience (812.43)
• If involved in a terminated trial,
explanation of circumstances (812.43)
• Signed Investigator Agreement (812.43)
• Financial disclosure information
(812.43)
Investigator Documentation
• IRB approval documentation (812.42)
• Provide the investigator with the
investigational plan and report of prior
investigations of the device (812.45)
• Other records (ICH):
– Local lab certification, normal ranges
– IRB membership roster
– Medical license
Periodic Visit Planning
• Participants
– Study coordinator
– Principal investigator
– Technicians
• Timing
– Follow monitoring plan
– Flexibility for problem sites
– First visit early
Periodic Visit Planning
• Materials
– Protocol
– List of enrolled patients
– Reference manuals
– Site specific material/documents
– Office supplies
• Assigned work space
• Assigned time with investigator and
trial staff
Periodic Visit Objectives
• Review compliance with protocol, GCPs,
and sponsor SOPs
• Review data
• Review investigational product
• Verify adequacy of facilities & resources
• Review essential (regulatory) documents
Protocol/GCP Compliance
• Protocol deviations explained (812.140)
• Enrolling only eligible patients
• Informed consent obtained before each
subject’s trial participation (and case
history statement, 812.140)
• All required reports to sponsor and IRB
• Adverse events appropriately reported
Data Review
• Source data are accurate, complete, and
up-to-date
• Compare accuracy and completeness of
CRF entries to source data
• Visits not done and tests not conducted
clearly reported as such on CRF
• All withdrawals and dropouts are
reported and explained on the CRFs
Data Review (cont)
• Ensure appropriate CRF corrections are
made, initiated, dated and explained (if
necessary)
• Member of trial staff authorized by
investigator to make corrections should
be documented
CRF Review
• First Pass
– All pages present
– Headers complete and accurate
– Missing fields flagged
• Primary Review
– All applicable data cross-checked with source
documentation
– Concomitant medications are spelled correctly
and have correct dosage
CRF Review (cont)
• Compliance Review
– Visits within protocol-defined window
– All procedures done
– Adequate explanations for protocol deviations
– Evidence of PI involvement in the trial
– Continuing adverse events followed-up
CRF Review (cont)
• Logic Check
– Data is within the expected range
– Medical history conditions and adverse events
requiring treatments have concomitant
medications listed
– Redundant CRF fields are consistent with each
other
– Primary efficacy response follows an expected
pattern
Investigational Product
• Storage conditions acceptable
• Supplied only to eligible patients
• Receipt, use and return are controlled
and documented (812.140)
• Exposure of each subject to the device
is documented (date and time of each
use, 812.140)
Facilities and Resources
• Ensure investigator and trial staff are
adequately informed about the trial
• Investigator and trial staff are
performing specified trial functions (not
delegated to unauthorized persons)
• Reporting subject recruitment rate
Close-Out Visit Activities
• IRB notified of trial closure
• Final device reconciliation, return or
disposal performed
• All CRFs submitted and final data
queries resolved
• Subject study files are complete
Close-Out Visit Activities
• Regulatory and administrative study
files are complete
• Record retention period discussed:
– Accessible to FDA and Sponsor
– Minimum of 2 years after the date the investigation
is terminated or completed or the date the records
are no longer needed to support a PMA (812.140)
– Records custody can be transferred in writing FDA notified in 10 days (812.140)
Monitor Report
• Should submit a written report to the
sponsor after each trial-site visit or trialrelated communication
• Include date, site, monitor name, name of
investigator and/or other staff contacted
• Include summary of what was reviewed
Monitor Report
• Also includes the following items:
– Significant findings
– Deviations and deficiencies
– Conclusions
– Actions taken or to be taken
– Actions recommended to secure compliance
Recent FDA Warning Letter
“There were no existing Standard
Operating Procedures for the internal
review and investigation of deficiencies
identified through the field clinical
monitoring reports.”
Source: CDRH Warning Letter to Cordis Corporation (July 7, 2004)
Recent FDA Warning Letter
“Even though your monitor did not check
the site device log during the March 13-14,
2001 site visit, in the visit report dated
April 25, 2001, the monitor stated that the
device accountability records at clinical
site [redacted] of the [redacted] Study had
been determined by the monitor to be
accurate and complete.”
Source: CDRH Warning Letter to Boston Scientific Corporation (August 22, 2004)
Warning Letter Citations on
Monitoring (2003-04)
7
No SOPs
6
5
Inadequate
4
Visits not
documented
3
Did not
follow SOPs
2
AEs not
investigated
1
Other
0
Citations: 24
Source: Nancy Starks, Clinical Device Group
Common Site
Problems and
Findings
Site Audit Findings - CDRH
60%
50%
40%
00
01
03
30%
20%
10%
0%
Failure to Follow
Investigational
Plan
Protocol
Deviations
Inadequate
Consent
Inadequate
Device
Accountability
Lack IRB/FDA
Approval
Source: ACRP Medical Device BIMO Workshop 2002 and MN ACRP Presentation 09/2004
Site Audit Findings - CDER
35%
30%
25%
20%
99
02
03
15%
10%
5%
0%
Protocol
Deviations
Inadequate
Record Keeping
Inadequate
Consent
Inadequate Drug
Accountability
Inadequate
Capture of AEs
Source: FDA - DIA 2000 and ACRP 2004
2003 Audit Comparison
Device
(353)
Drug
(368)
Protocol Deviations
38%
25%
Inadequate Consent
21%
9%
Inadequate Investigational
Product Accountability
18%
5%
Common Site Problems
• Slow/erratic enrollment or follow-up
• Patients lost to follow-up
• Protocol non-compliance
– Enrollment of ineligible patients
– Violation of visit schedule, treatment
procedures, etc.
– Required adjunctive procedures not performed
or adequately documented
– Disallowed concomitant therapy
Common Site Problems
• Data Problems . . .
– Incomplete documentation of dropouts
– Missing or incomplete date
– Erroneous or inconsistent data
– Errors in units recorded or conversion of units
– Discrepancies between data in CRF and
source documents
– Inadequate source documents
– Corrections made incorrectly or not properly
documented
Common Site Problems
• Data Problems . . .
– Abnormal values not documented
– Inter-current illnesses and/or concomitant
drugs not documented
– Complications/adverse events not properly
documented
• Device/drug accountability incorrect
or incomplete
Addressing
Non-Compliance
Non-Compliance
“A sponsor who discovers that an investigator
is not complying with the signed agreement,
the investigational plan, the requirements of
this part or other applicable FDA regulations,
or any conditions of approval imposed by the
reviewing IRB or FDA shall promptly either
secure compliance or discontinue shipments
of the device to the investigator and terminate
the investigators participation in the
investigation.” (812.146)
Non-Compliance
• Repeated but minor non-compliance
usually due to overwork, inexperience
• Spend additional time on protocol and
GCP training
• Talk to staff supervisor and investigator
about additional personnel resources
• Bring a co-monitor for reinforcement
Non-Compliance
• If negligence or apathy on part of
investigator, inform IRB and plan site
closure unless improvement
• If data integrity is compromised, withhold
payment
• Withdraw consideration for future trials
Tools to Improve Conduct
• Report visit findings in follow-up letter
to investigator and study coordinator
• Trial delegation authorization list
• Protocol deviation/explanation list
• File all relevant telephone contact
reports at the site
Tools (cont)
• Study specific source documents
• Annotated case report forms
• Trial newsletter/website
• Frequently asked questions document
Detecting Fraud
and Misconduct
FDA Definition of
Research Fraud
• Research misconduct means
falsification of data in proposing,
designing, performing, recording,
supervising or reviewing research, or
in reporting research results.
• The FDA uses the terms “fraud” and
“misconduct” interchangeably
Definition (cont)
• Per FDA, falsification includes acts of
omission and commission
• Omission = consciously not revealing
all data
• Commission = consciously altering or
fabricating data (eg, lab values, lesion
counts, etc)
Definition (cont)
• Fraud does not include honest error
or honest differences in opinion
• Per the FDA, deliberate or repeated
noncompliance with the protocol and
GCP can be considered fraud, but is
secondary to falsification of data
Prevalence of Fraud
• Difficult to determine but considered
rare
• Reported to significantly impact 1-5%
of pharmaceutical clinical trials - Frank
Wells, Medico Legal Investigations
(Reuters Health, Jan 2002)
• Only ~3% of FDA inspections uncover
serious GCP violations
Consequences of Fraud
• Sponsor – data validity compromised,
submission jeopardized, additional
costs
• Investigator – disqualification, fines,
incarceration, legal expenses, ruined
career
• Institution – lawsuits
• Subject – safety at risk, loss of trust in
clinical trial process
Consequences (cont)
• Fraudulent investigators are often used
by multiple sponsors on multiple trials
• A small number of investigators can
have a broad impact on many
submissions made by sponsors
• Disqualified investigator, Dr. Fiddes,
was involved in 91 submissions with
47 different sponsors
Why Does Fraud Occur?
• Not enough time or staff
• Not enough subjects
• Lack of GCP training and/or regulatory
oversight
• Laziness, loss of interest
• Money, greed
• Pressure to perform, publish
General Warning Signs
• High staff turnover
• Staff are disgruntled, fearful, anxious,
depressed, defensive.
• High pressure work environment
• Obsession with study payments
• Absent investigators
• Lack of GCP training
• Unusually fast recruitment
Data Identifiers
• Implausible trends/patterns:
– 100% drug compliance
– Perfect efficacy responses for all subjects
– Identical lab/ECG results
– No SAEs reported
– Subjects adhering perfectly to visit
schedules
Data Identifiers (cont)
• Site data not consistent with other
centers (statistical outlier)
• Perfect diary cards, immaculate CRFs
• All source records & CRFs completed
with the same pen
• Source records lack an audit trail - no
signatures and dates of persons
completing documentation
Identifiers (cont)
• Subject handwriting and signatures
are inconsistent across documents
(consents, diaries)
• Questionable subject visit dates
(Sundays, holidays, staff vacations)
• Impossible events (eg, randomization
before drug delivery)
• Data contains “digit preference”
Identifiers (cont)
• Subject visits cannot be verified in the
medical chart, appointment schedule,
or billing records
CRA Strategies for
Detecting Fraud
• Ask for all information (data) pertinent
to the study (CRFs, study specific
source worksheets, clinic charts, signin sheets, lab requisitions, shipping
records)
• Accept no copies – review originals
whenever possible
• Get technical – read lab reports, xrays, ECGs – don’t just inventory
Detection Strategies (cont)
• Expect fraud – start from the
assumption that records are bogus
and work backwards
• Question missing, altered, and/or
inconsistent data – offer to retrieve
records yourself, keep pulling on loose
ends and see what unravels
• Don’t be intimidated – challenge the
site to explain suspicious data
Detection Strategies (cont)
• Be suspicious of blame shifting –
remind the investigator that he/she is
responsible for study conduct
• Cultivate whistleblowers – pay
attention to staff complaints, listen to
grievances, establish rapport, and be
approachable
What Do I Do If I
Detect Fraud?
• Follow company SOPs
• Carry out remainder of visit as usual
• Collect supporting documentation
• Call supervisor/study manager when you
are away from the site
• Challenge but do not accuse
What Do I Do?
• Write a fact-based summary of your
findings when you return to the office
• Call in independent auditors to confirm
suspicions
Electronic Records
and Signatures
History
• Process started in 1991 - Pharma
industry and FDA met to determine
how to accommodate paperless record
systems within the GMP regulations
• Created Task Force on Electronic
Identification and Signatures to
develop a uniform approach to
electronics records and signatures for
all FDA program areas
History (cont)
• 1992 - FDA announced it was
considering the use of electronic
signatures and requested comments
• 1994 - Proposed rule published and
additional comments requested
• Final rule effective August 20, 1997
Importance to Industry
• Electronic records prevalent across
many manufacturing, laboratory and
clinical practices
• Benefits are enormous:
– Increased speed of information exchange
– Cost savings
– Reduced errors
– Improved process control
Scope of the Final Rule
• Provides criteria under which agency
will consider electronic records and
signatures equivalent to paper
• Applies to any record required to be
maintained or submitted to the agency
• Computer systems and documentation
maintained under this part are subject
to FDA inspection - legacy systems are
not exempt
Implementation
• If requirements of the rule are met,
electronics records & signatures can be
used in lieu of paper and handwritten
signatures in whole or in part
• FDA has a list of documents that it can
accept submitted in electronic form
• Use of electronic records and their
submission to FDA is voluntary
Definitions
• Electronic record - any combination of
text, graphics, data, audio, or pictorial
information represented in digital form
that is created, modified, maintained,
archived, retrieved or distributed by a
computer
• Electronic signature - a compilation of
any symbol(s) executed to be the
legally binding equivalent of an
individual’s handwritten signature
Definitions (cont)
• FDA defines closed and open systems
- difference is in who controls system
• Closed system = people responsible
for data content also control system
• In an open system, data could reside
for some period of time on a system
that is outside the control of the
organization that owns the data
System Requirements
• System must be “validated” to ensure
accuracy, reliability and consistency
• Ability to generate accurate and
complete copies of records (readable
form suitable for inspection)
• Protection and ready retrieval of records
throughout the archival period
• Limited access to authorized individuals
System Requirements (cont)
• Use of audit trials (computer-generated,
time-stamped) to record the creation,
modification and deletion of records
• Audit trial documentation must be
retained and available for agency
inspection
• Persons using and maintaining
systems are trained to perform their
assigned tasks
System Requirements (cont)
• Establishment and enforcement of
written policies that hold individuals
responsible for actions initiated under
their electronic signature
• Systems documentation is controlled
(access and distribution) and audit trial
maintained for modifications
• Encryption may be necessary for open
systems to ensure confidentiality
Signature Requirements
• Signed electronic records need to have
the following information:
– Printed name of the signer
– Date and time of signature
– Meaning of the signature (i.e., review,
approval, authorship)
Signature Requirements (cont)
• Electronic signature cannot be excised,
copied or transferred
• Unique to one individual (cannot
reused or reassigned)
• An organization must verify individual
identity before an electronic signature
is established and assigned
Signature Requirements (cont)
• Sponsors need to “certify” to FDA
when electronic signatures will be used
as the legally binding equivalent of
handwritten signatures
Signature Controls
• Best control is based on biometrics
• If not, at least two distinct components
should be employed such an
identification code and password.
• Maintain uniqueness of combined
identification code and password
• Identification codes and passwords are
periodically recalled or revised
Signature Controls (cont)
• Have a procedure for lost devices that
generate ID codes
• Periodically test ID devices
Interactive Case
Studies
References
This presentation and related references
are posted on my website at:
www.pbelow-consulting.com/
monitoring.html
Contact Information
• E-mail: [email protected]
• Home office phone: (952) 882-4083
• Don’t hesitate to call me with follow-up
questions!