Medical Alley Advanced Monitoring Workshop

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Medical Alley Advanced Monitoring Workshop

• Paul Below
• P. Below Consulting, Inc.
• October 19, 2005

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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

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• This presentation and related references are
  posted on my website at
• www.pbelow-consulting.com/monitoring.html

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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

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Objectives

• Interactive case studies of real-life monitoring
  situations

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The Role of Monitoring in Good Clinical Practices
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Why Do We Monitor?

• Required to by regulation
• Ensure the acceptance of trial data by regulatory
  authorities (i.e., FDA)

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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

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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

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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)

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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

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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

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GCP Guidance Documents

• FDA Information Sheets (www.fda.gov/oc/ohrt/irbs/d
  efault.htm)
• Guideline for the Monitoring Clinical
  Investigations (January 1988)
• ICH Guidelines for Good Clinical Practice
  (Published in Federal Register - May 9, 1997)

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FDA Guidance

• Represents the agencys 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

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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

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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)

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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)

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Monitoring Plan (cont)

• Monitoring plan based on
• Trial objectives, design, endpoints
• Trial complexity
• Number/location of investigators
• Type of investigational product
• Disease under study

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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

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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)

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Monitor Selection

• Need not be qualified to diagnose or treat
  disease under study
• Thoroughly familiar with test article, protocol
  and informed consent, sponsors SOPs, and GCPs
  and FDA regulations
• Qualifications should be documented

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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)
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Outstanding Monitor Traits

• Quick scientific learners
• Independent problem solvers
• Can hack the travel
• Can see the forest and the trees
• Regulatory experts
• Technologically proficient

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Activities Involvedin On-Site Visits
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On-Site Visit Types

• Pre-Investigation
• Periodic Monitoring
• Close-Out

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Selection of Investigators

• A sponsor shall select investigators qualified
  by training and experience to investigate the
  device (812.43)

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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

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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

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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

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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 FDAs
  Bioresearch Monitoring Program
• www.fda.gov/cder/regulatory/investigators/default
  .htm

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Pre-Investigation Visit

• Location
• All facilities where trial conduct will occur
• Materials
• Investigators Manual
• Device
• Agenda

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Pre-Investigation Visit

• Participants
• Principal Investigator/Co-Investigators
• Study coordinator/research nurse
• Other medical staff (technicians)

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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

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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

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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

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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)

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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

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Periodic Visit Planning

• Participants
• Study coordinator
• Principal investigator
• Technicians
• Timing
• Follow monitoring plan
• Flexibility for problem sites
• First visit early

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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

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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

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Protocol/GCP Compliance

• Protocol deviations explained (812.140)
• Enrolling only eligible patients
• Informed consent obtained before each subjects
  trial participation (and case history statement,
  812.140)
• All required reports to sponsor and IRB
• Adverse events appropriately reported

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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

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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

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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

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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

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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

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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)

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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

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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

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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)

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Monitor Report

• Should submit a written report to the sponsor
  after each trial-site visit or trial-related
  communication
• Include date, site, monitor name, name of
  investigator and/or other staff contacted
• Include summary of what was reviewed

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Monitor Report

• Also includes the following items
• Significant findings
• Deviations and deficiencies
• Conclusions
• Actions taken or to be taken
• Actions recommended to secure compliance

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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)
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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)
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Warning Letter Citations on Monitoring (2003-04)
Source Nancy Starks, Clinical Device Group
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Common Site Problems and Findings
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Site Audit Findings - CDRH
Source ACRP Medical Device BIMO Workshop 2002
and MN ACRP Presentation 09/2004
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Site Audit Findings - CDER
Source FDA - DIA 2000 and ACRP 2004
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2003 Audit Comparison

• Device Drug
  (353) (368)
• Protocol Deviations 38 25
• Inadequate Consent 21 9
• Inadequate InvestigationalProduct
  Accountability 18 5

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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

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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

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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

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Addressing Non-Compliance
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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)

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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

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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

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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

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Tools (cont)

• Study specific source documents
• Annotated case report forms
• Trial newsletter/website
• Frequently asked questions document

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Detecting Fraud and Misconduct
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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

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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)

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Identifiers (cont)

• Subject visits cannot be verified in the medical
  chart, appointment schedule, or billing records

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CRA Strategies for Detecting Fraud

• Ask for all information (data) pertinent to the
  study (CRFs, study specific source worksheets,
  clinic charts, sign-in sheets, lab requisitions,
  shipping records)
• Accept no copies review originals whenever
  possible
• Get technical read lab reports, x-rays, ECGs
  dont just inventory

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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
• Dont be intimidated challenge the site to
  explain suspicious data

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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

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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

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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

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Electronic Records and Signatures
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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

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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

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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

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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

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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

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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 individuals handwritten
  signature

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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

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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

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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

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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

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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)

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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

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Signature Requirements (cont)

• Sponsors need to certify to FDA when electronic
  signatures will be used as the legally binding
  equivalent of handwritten signatures

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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

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Signature Controls (cont)

• Have a procedure for lost devices that generate
  ID codes
• Periodically test ID devices

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Interactive Case Studies
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References

• This presentation and related references are
  posted on my website at
• www.pbelow-consulting.com/monitoring.html

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Contact Information

• E-mail paul_at_pbelow-consulting.com
• Home office phone [phone]
• Dont hesitate to call me with follow-up
  questions!