Transcript Conflict of Interest - Drexel University College of Medicine

care
community
Overview of Good
Clinical Practice
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Welcome
• Please silence cell phones
• Please limit exits and entrances
2
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Essential Study
Documents
Study Documentation
DWD & Associates
Essential Study Documents
• Essential Documents are those
documents that individually and
collectively permit evaluation of the
conduct of a trial and the quality of the
data produced.
ICH GCP E6 guidance 1997
DWD & Associates
Essential Study Documents
• Purpose:
– demonstrate the compliance of the
investigator, sponsor, and monitor with GCP
and applicable regulatory requirements.
– Assist in the successful management of a trial
by the investigator, monitor, and sponsor
DWD & Associates
Essential Study Documents
• Grouped into 3 sections
– Before the clinical phase of the trial begins
– During the clinical conduct of the trial
– After completion or termination of the trial
DWD & Associates
Essential Study Documents
• Both Sponsor and investigator should
establish a study file at the beginning of
the trial
• At close-out of trial
– Confirm that all necessary documents are in
the appropriate files
• Documents may be subject to an audit
• Acceptable to combine some of the
documents
DWD & Associates
Before The Clinical Phase Of
The Trial
Document
Investigator
Sponsor
Investigator’s brochure
X
X
Signed protocol and
amendments, if any, and
sample CRFs
Information given to trial
subjects
-Informed consent form
X
X
X
X
X
X
X
-Any other written information
Advertisement for recruitment
DWD & Associates
Before The Clinical Phase Of
The Trial
Document
Investigator
Sponsor
Financial aspects of trial
X
X
Insurance statement
(where required)
Signed agreement
between involved parties
X
X
X
X
Dated, documented
approval/favorable
opinion of IRB/IEC
X
X
DWD & Associates
Before The Clinical Phase Of
The Trial
Document
Investigator
Sponsor
X
Where
required
Regulatory authority
authorization/approval/notifi
cation of protocol (where
required)
CV of investigator and subinvestigators
Where
required
Where
required
X
X
Normal values/ranges for
medical/lab/tech procedures
X
X
IRB/IEC composition
DWD & Associates
Before The Clinical Phase Of
The Trial
Document
Investigator
Sponsor
Medical/lab/tech procedures/tests
-Certification or accreditation or
established quality control or other
validation
Where
required
X
Sample of labels attached to
investigational product containers
X
X
Instructions for handling of
investigational products and trialrelated materials
X
X
DWD & Associates
Before The Clinical Phase Of
The Trial
Document
Shipping records for investigational
products
Investigator
Sponsor
X
X
Certificate of analysis of investigational
product shipped
Decoding procedures for blinded trials
Master randomization list
DWD & Associates
X
X
X
(third party if
applicable)
X
(third party if
applicable)
Before The Clinical Phase Of
The Trial
Document
Investigator
Pretrial monitoring report
Trial initiation monitoring
report
DWD & Associates
Sponsor
X
X
X
During the Trial
Document
Investigator
Sponsor
Investigator’s Brochure Updates
X
X
Revisions to protocol/CRF /IC form/
written information /advertisement
X
X
IRB/IEC approval of any
amendments/revisions
X
X
CVs of any additional
investigators/sub-investigators
X
X
DWD & Associates
During the Trial
Document
Updates to normal values/ranges
Updates of medical/lab/tech
procedures/tests
Documentation of investigational
product
Certificates of analysis for new
batched of investigational product
DWD & Associates
Investigator
Sponsor
X
X
Where
required
X
X
X
X
During the Trial
Document
Investigator
Monitoring Visits
X
Relevant communications other
than site visits
-letters, meeting notes, telephone
calls
X
Signed informed consent forms
X
Source Documents
X
DWD & Associates
Sponsor
During the Trial
Document
Signed, dated, and
completed CRFs
Documentation of CRF
corrections
Notification by investigator
to sponsor of SAEs and
related reports
DWD & Associates
Investigator
Sponsor
Copy
Original
Copy
Original
X
X
During the Trial
Document
Investigator
Sponsor
Notification by sponsor &/or
investigator, to regulatory authorities
and IRB of unexpected SAEs and
other safety info
Where
required
X
Interim or annual report to IRB
X
Where
required
Subject screening log
X
Where
required
DWD & Associates
During the Trial
Document
Investigator
Sponsor
Subject identification code
X
Subject enrollment log
X
Investigational product accountability
at site
X
X
Signature sheet
X
X
Record of retained body fluids/tissue
samples
X
X
DWD & Associates
After Completion or Termination
of the Trial
Document
Investigational product accountability
at site
Documentation of investigational
product
Completed subject identification code
list
Investigator
Sponsor
X
X
If destroyed at
site
X
X
Audit certificate (if required)
X
Final trial close-out monitoring report
X
DWD & Associates
After Completion or Termination
of the Trial
Document
Treatment allocation and
decoding documentation
Final repot by investigator
to IRB and to regulatory
authority where applicable
Clinical Study Report
DWD & Associates
Investigator
Sponsor
X
X
If applicable
X
Regulatory Binders
• CV and current medical licensesw for the PI, all sub-I, and any
others listed on Form FDA 1572
• A completed, signed and dated copy of Form FDA 1572, plus
completed and signed copies of any amended Form FDA 1572
• Asigned, dated copy of the official study protocol, plus signed dated
copies of any subsequent amendments
• IRB approval letter for protocol and consent and any approved
advertisement for subject recruitment.
• IRB membership roster
• Investigator’s Brochure
• Lab CAP and CLIA certifications. CV and license for lab director,
reference ranges for lab tests
• Drug inventory
Regulatory Binders
• Correspondence to or from sponsor, PI, IRB, Investigational Drug,
Pharmacy and subjects
• Screening log
• Patient log
• Monitoring reports
• Signature log and delegation sheets
• SAE reports and supporting documents
• IRB notification of IND safety reports
• All correspondence should be stamped with date of receipt
Drexel University College of Medicine, Guidelines for the conduct of Clinical Trials,
Regulatory Documents 4/27/2004.
Source Documentation
• Importance of Documentation
– Necessary for the reconstruction, evaluation,
and validation of clinical findings,
observations, and other activities during a
clinical trial –ICH 1.52
– Substantiates the integrity of trial data,
confirm observations that are recorded and
confirm the existence of subjects.
Source Documentation
• Purpose:
– To record a subject’s history, diagnosis, and
medical management
– Enable monitors to verify that trial data are
accurate, complete, and verifiable
– Permit a reconstruction of the trial
Examples of Source Documents
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Past Medical History
Patient medication record
Admission assessment
Nursing records
Vital signs
Lab report that physician initials and dates
ECG
Consultant reports
What is not considered source
data?
• Lab print-out
• X-ray report
• Others?
The Electronic Medical Record
• 21 CFR, Part 11
– Applies to records in electronic form that are
created, modified, maintained, archived, or
retrieved for FDA regulated purposes.
– Validation
– Limited access
– Secure, computer-generated time stamped
audit trails.
The Electronic Medical Record
• Treated same as paper with regards to
documentation.
• Available to the FDA for audit.
• Password and username security.
Source Documentation
• Apply ALCOA to achieve data quality
– Attributable
– Legible
– Contemporaneous
– Original
– Accurate
Source Documentation
• Source documents should be the original
document. If a copy is used as a source
document, it should be certified that it was
verified to be an exact copy of the original,
having all of the same attributes and information
as the original.
• If the original document is retained elsewhere in
the study file, the copy does not need to be
certified.
Source Documentation
• Must have:
– Subject number or identifier
– Date/time of collected data point
– Data
– Signature of person making observation
• Unless data is automated (e.g. Dinamapp printout)
Recording of Source Data
• Must be permanent
– Black ink or typed
• Protected from unauthorized change
– Nothing that can be erased
• Sequence should be chronological
• If additions need to be made, they need to
be signed and dated.
• Original entry must be visible if corrections
are done. (audit trail)
Recording of Source Data
• Corrections should be made according to
GCP
– Draw a single line through data to be
corrected, record new data, initial and
date correction.
• If reason for change is not obvious, it
should be explained.
• If data are transcribed (e.g. lab data), the
source data is the original laboratory
report.
Recording of Source Data
• Source documents should not be removed
from the investigator’s site.
• Source documents should never be
destroyed.
• The first place the data is recorded is the
source document.
Recording of Source Data
• CRF as source document
– Data may be recorded directly onto a CRF
with no prior written or electronic record.
– Any data that is to be recorded directly onto a
CRF should be identified in the protocol as
per ICH GCP.
Recording of Source Data
• When a subject drops out of a study
– Document the reason for dropping out
– Keep a record of attempted and actual patient
contacts
– Obtain all follow-up information where
possible
– If unable to obtain follow-up, document the
subject as lost to follow-up.
Source Documentation Do’s
and Don’ts
• Do’s:
– Do print legibly.
– Do use a black ballpoint pen.
– Do make sure your letters and numbers are legible
and easy to read.
– Do complete all sections of each page as requested.
– Always use a 24 hour clock.
– Dates should be recorded in the day, month, year
format (dd/mmm/yyyy).
Source Documentation Do’s
and Don’ts
• Do’s
– Checkboxes should be marked with a
checkmark or an X
– Do use only accepted medical abbreviations.
Source Documentation Do’s
and Don’ts
• Don'ts
– Don’t add information at a later date without indicating
that you did so.
– Don’t date the entry so that it appears to have been
written at an earlier time.
– Don’t add inaccurate information.
– Don’t destroy original documents even if they require
error correction.
– Don’t alter information.
– Don’t double document paper and electronic.
Source Documentation Do’s
and Don’ts
• Don’ts
– Don’t leave empty lines or spaces.
• Draw a line through the empty line or space to
prevent charting by someone else.
– Don’t write in the margins
• If you need to record additional information, use a
progress notes page or use a comments space.
– Don’t predate or postdate information.
Where can data be found?
• It continues with the Case Report Form or data
collection form
• CRFs provide the means to collect S/E data
required by the protocol which is then
transferred to a data base to ensure quality and
integrity of the trial
• Why are there so many CRFs?
– The shoe box and the IRS audit phenomenon
– Attestation to credibility, veracity, compliance, etc.
• Organization of forms
– Amount of data to be collected
– Grouping of forms by visit
Special Considerations: The eCRF
• The computerized eCRF replaces the paper
CRF.
• Sponsor provided computers used only for
eCRF entry.
• Computers should be secured within the office.
• Password and username security is critical.
Investigator-Initiated Clinical
Research
• In collaboration with your statistician,
develop case report forms to accurately
collect data
– Why?
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Record of participant safety
Record of compliance
Record of procedures carried out
Facilitates analysis of the data and writing the
paper(s)
• What else???
CRF Recording Practices
• Do not use records from one subject’s book for another
subject.
• Do not use photocopies of a CRF as a source doc or as
a replacement for a CRF.
• If data are not available, record NA.
• If a test or item was not done, indicate ND
• If no data for a particular CRF is collected, complete the
header of the CRF and draw a diagonal line across the
entire page to indicate not done. Do not obscure the
header section.
CRF Recording Practices
• Do not write in the margins.
• Do not write on the pink or yellow copies of the
CRF. Only write on the white page.
• Use only black ballpoint pen.
• Place cardboard or a similar insert beneath the
record on which entries are being made.
• Use only standard medical terminology and
abbreviations.
CRF Recording Practices
• Numeric values
– Must correspond to source documents.
– Must be positioned using the printed decimal
where applicable.
– It is not necessary to enter zeros in each box.
• Times must be recorded using a 24 hour
clock.
• Complete dates/times should be provided.
– When dates/times are unknown, record UNK
CRF Recording Practices
• Investigator must sign and date the Conclusion
of Subject Participation record to certify that
he/she has examined all the pages of the CRF
and that all data recorded are accurate and
complete.
– Date of review must reflect review of corrected
information.
– AE record and Death Report record require a
signature also.
Source Data Verification
• What is it?
– Procedures carried out to ensure that the data contained in the
CRF is consistent with that in the source documents.
• Why do it?
– Establish the existence of the research participant in the trial and
his/her eligibility
– Ensure that source data exists for all participants
– Ensure protocol compliance
– Systems with procedures should be implemented that assure the
quality of every aspect of the trial. ICH – 2.13
Source Data Verification
• Objectives:
– To prove the existence of the subjects
– To prove their eligibility to participate in the
study
– To confirm that they gave consent
– To confirm that relevant data have been
accurately transferred from the source
document to the CRF
– To ensure that there is no bias caused by
omitting data
Source Data Verification
If the study is
going to be
monitored
anyway, why
should we
spend the time
to double check
Source Data Verification
• Site monitors review of CRFs is not always
timely or comprehensive.
• Improve quality of data collected.
• By verifying your own data, you can
recognize trends or areas that need to be
improved.
Source Data Verification
• What should be verified?
– Research sites should compare source documents to
the protocol and to the CRFs before starting the study
to make sure they are gathering the correct
information at the correct timepoints.
– After the study, the source documents should be
compared to the CRFs to verify all data.
– Verification procedures should be outlined in an SOP.
Source Document Verification
• All verification needs to be documented.
– Checklist form
– Signatures/dates of verification
– Different person who verifies than who
recorded data.
– System for correcting error
Source Document Verification
What do I
look for?
CRF vs. SD Review
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Demography
Informed Consent
Eligibility
Medical History
Study Medication
Concomitant Medication
Lab & Diagnostic test results
Adverse Events
All subjects accounted for
CRF vs. SD Review
• Protocol Adherence
– Protocol Deviation
• An incident involving noncompliance with the
protocol but does not affect the subject’s rights,
safety, welfare, or the integrity of the resultant
data.
– Protocol Violation
• More serious, may involve critical study
parameters.
• May render a subject ineligible
• Affects the subject rights, safety, welfare or data
integrity.
DWD & Associates
Archiving Requirements
• If an archive is not up to standard it will
have a negative impact on the outcome of
a study audit.
DWD & Associates
Archiving Responsibilities
• Sponsor
– Retain all sponsor specific essential documents
– Retain according to regulatory requirement of the
countries where the product is approved
– Retain for 2 years after discontinuation of the clinical
development of a product.
– Transference of ownership of the compound and
documents must be reported to appropriate
authorities.
DWD & Associates
Archiving Responsibilities
• Sponsor
– Essential documents should be retained until at least
2 years after the last approval of a marketing
application (NDA) in an ICH region and until there are
no pending or contemplated marketing applications in
an ICH region.
– Inform the investigator in writing of the need for
record retention and when the records can be
destroyed.
DWD & Associates
Archiving Responsibilities
• Investigators
– Maintain all essential documents as per GCP
– Prevent destruction of essential documents
– Retain documents until sponsor notification that
documents can be destroyed
– Have documents available for access by monitor,
auditor, IRB, or regulatory authority as requested.
DWD & Associates
care
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Adverse Events
Evaluating Safety
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Adverse Events
Serious Adverse Events
Devices
Federally Funded Research
Adverse Drug Experiences
Protocol Violations/Deviations
When a proposed drug’s benefits outweigh
known risks, the FDA’s Center for Drug
Evaluation and Research considers it safe
enough to approve.
Benefit vs. Risk: How CDER approves new drugs
ADVERSE EVENTS
Adverse Events
• Definition: (from ICH GCP 1997)
– Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product
and which does not necessarily have a causal relationship
with this treatment. An adverse event can therefore be any
unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally
associated with the use of a medicinal (investigational)
product, whether or not related to the medicinal
(investigational) product.
Interpretation
• Changes in the clinical condition or worsening of
conditions present at the onset of the study
• Patient deterioration due to the primary illness
• Inter-current illness
• Drug interactions
• Events related or possibly related to concomitant
medication
• Important abnormal laboratory values which the
clinician considers clinically relevant
Adverse Events
• Primary role of the Investigator
• Challenges in identifying and reporting
SERIOUS ADVERSE
EVENTS
Serious Adverse Event (SAE)
• Definition (from ICH GCP 1997)
– Any untoward medical occurrence that at any
dose:
• Results in death
• Is life-threatening
• Requires inpatient hospitalization or prolongation
of existing hospitalization
• Results in persistent or significant
disability/incapacity
• Is a congenital anomaly/birth defect
Additional FDA Description
• Based upon appropriate medical
judgment, jeopardize the patient or subject
and may require medical or surgical
intervention without hospitalization.
21 CFR Part 312.32
Responsibilities of Sponsors
• The sponsor is responsible for the ongoing
safety evaluation of the investigational
product.
• Must notify the FDA and all participating
investigators of
– Any AE that is both serious and unexpected.
– Any finding from tests in animals that suggest
a significant risk for humans.
Responsibilities of Investigators
• Know the definitions of an AE/SAE for the individual
protocol and IRB.
• Report all unexpected SAEs to the sponsor except
those that the protocol identifies as not needing
immediate reporting.
• Report to the sponsor any AEs and/or laboratory
abnormalities identified in the protocol as critical to
safety evaluations.
• Supply sponsor and IRB/IEC with information
regarding serious adverse events
Responsibilities of Investigators
• Ensure that members of staff are aware of the
procedure for reporting AE/SAE
• Ensure that all AE/SAE documentation are included in
the study file
• AE/SAE to be followed up until outcome is known
• Assign causality
• Review IND Safety Updates received from sponsor
and forward to IRB
Serious vs. Severity
• Serious
patient outcome
• Severity
ADL
Reporting Serious Adverse Events
• Investigator
– Established procedure for reporting
– Report to Sponsor and IRB immediately
• Sponsor
– Notify the FDA no later than 7 calendar days
after Sponsor’s initial receipt of information.
• FDA Form 3500A
– Notify Investigators through IND Safety
Updates
FDA Guidance – IND Studies
•What is an unanticipated problem?
– AE represents a serious unexpected event
that is rare in absence of drug exposure.
– Signal that events were not isolated
occurrence
– Expected event that occurs with greater
frequency
– Event that results in modified IB
Guidance for Clinical Investigators, Sponsors, and IRBs Adverse Event Reporting –
Improving Human Subject Protection, Draft. April, 2007
Reporting to IRB – FDA Guidance IND
Studies
• Sponsor is in best position to review and
analyze AE information
• Investigator may rely on sponsor’s
assessment and provide to the IRB a
report prepared by the sponsor
• If sponsor reports directly to the IRB, the
investigator is not expected to duplicate
reporting.
DEVICE RELATED EVENTS
Device Regulation
• 21 CFR 814
• PMA: any premarket approval application
for a class II medical device.
Device Related Serious
Illness/Injury
• Life threatening
• Results in permanent impairment/damage
to body function or structure
• Necessitates medical/surgical intervention
to prevent permanent impairment, damage
of body function/structure
Caused or Contributed
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Device failure
Manufacturer defect
Malfunction
Improper/inadequate design
Improper/inadequate labeling
Use error
Medical Device Reporting
• Reported within 10 working days of learning of it
• Sponsor immediately conducts evaluation and reports
to FDA, all reviewing IRBs and Investigators
• Reported through Center For Devices And
Radiological Health
• Suspected medical device related deaths need to be
reported to both FDA and manufacturer.
• Use form MEDWATCH Form 3500A
FEDERALLY FUNDED
RESEARCH
45 CFR part 46 Reporting Requirement
• Unanticipated Adverse Event
• Unanticipated problem involving risks
to subjects or others
Unanticipated Problems
• Unexpected
• Related or possibly related to participation
in research
• Increased concern about risk of harm
HHS Definition of AE
• Any untoward or unfavorable medical
occurrence in a human subject, including
any abnormal sign, symptom or disease,
temporally associated with the subject’s
participation whether or not related to
subjects participation.
AE is Reported if…
• Unexpected given protocol-related
documents and the characteristics of the
subject population being studied
• Related or possibly related to participation
in the research
• Places subjects or others at a greater risk
of harm
Examples of AEs that are Unexpected
• Liver Failure due to diffuse hepatic
necrosis if protocol documents do not
identify liver disease as a potential
adverse event
• Liver failure due to hepatic necrosis even if
protocol information refers to elevated
hepatic enzymes
Unanticipated Problems that are Not AEs
• An investigator’s laptop is stolen with
identifiable data regarding illicit drug use.
• Dosing error where subject receives a
dose 10 times higher than dose indicated
by IRB approved consent.
HHS Guidance
• January 15, 2007
• Provides greater clarity of reporting
requirements and definitions
• Provides guidance to IRB procedural
requirements
• Reporting requirements related to external
adverse events
POST-MARKETING EVENTS
Reporting Requirements
• Serious
• Unlabeled
• Related to use of drug
Adverse Drug Experiences
• AE associated with the use of a drug in
humans, whether or not considered
related including:
– AE used in course of professional practice
– AE occurring from drug overdose
– AE occurring from drug abuse
– AE occurring from drug withdrawal
– Failure of expected pharmacological action
Review of ADE
• Applicants with approved applications must promptly
review all ADEs
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Commercial marketing
Experience
Post marketing clinical investigations
Post marketing epidemiological/surveillance studies
Scientific literature
Unpublished scientific papers
• Written procedures for surveillance, receipt,
evaluation, and reporting of post marketing ADEs to
FDA
Examples
• IND study with marketed interacting drug
• Sponsor funded, Investigator Initiated
study using a marketed drug
• Investigator initiated study for off label use
Sponsor Reporting Requirements
• Post marketing studies
– 15-day alert report only if there is reasonable
possibility that it is related to the drug.
– Complete FDA Form 3500A for each patient
• IND #
• NDA #
ADE Reporting Process for Investigator
• Reporting process
– Print report
• Documentation is part of the study file
• When fax document to sponsor, keep fax
receipt as part of records.
• Take the next step and notify sponsor
IN SUMMARY
Best Practices
• Report it TODAY
• Processes with documentation of ALL
applicable regulations and guidance
• Awareness of international standards
• Sponsor has obligation to know what
CROs are doing
– Companies are manufacturers
Data
• FDAAA Clinical Trial Databases
• FDA Guidance Documents count!!!
Acknowledgement
Carol Krueger, CSO, RN – Compliance
Officer
Food and Drug Administration
care
community
research
teach
Quality Management in
Clinical Trials
Course Objectives
• Discuss key requirements and the purpose of
Standard Operating Procedures.
• Discuss the role of quality assurance in
investigator site study conduct.
• Describe the role of the study monitor in the
oversight of sponsor studies.
“Sites have an ethical responsibility to
conduct clinical trials with well-trained
staff, documented procedural systems,
and most importantly, making the time to
implement realistic quality assurance
processes.”
Thomas, Carolynn, Dean, T. Beth, Fowler, Donna,“Quality time: the art of QA program development
for research sites” Research Practitioner, Volume 4, number 6, p 219.
• Challenges for today’s research sites:
– Competitive enrollment among sites
– High cost of operations
– Shortages of qualified staff
– Increasing trial complexities
– Decreasing study budgets
Quality Management
• 5 areas
– Standard Operating Procedures
– Quality Assurance
– Monitoring
– Fraud
– FDA Inspections
Standard Operating Procedures
• It is a requirement of GCP that during the
conduct of a Phase I-IV clinical trial, the
responsible organization must employ
documented systems of quality control and
quality assurance, and ensure that the trial
adheres to written SOPs, with the objective that,
given the same raw materials, suitably qualified
individuals will achieve the same result by
following the step-by-step instructions contained
within the SOP.
Standard Operating Procedures
• Definition
– Detailed, written instructions to achieve
uniformity of the performance of a specific
function.
ICH GCP E6 Document
– A set of written instructions on how to perform
a certain task or action.
Standard Operating Procedures
• Purpose
– Ensure compliance with GCP and federal regulations
– Help to achieve maximum effectiveness of clinical operations.
– Ensure consistency, compliance, and accountability of personnel
at all levels of clinical research.
– Provide structured guidelines for implementing clinical trials.
– Regulate internal quality
– Aid in process improvements
Standard Operating Procedures
• After an SOP is approved
– All SOPs need to be reevaluated every 2
years at minimum and updated as needed.
– SOPs need to be filed in a central area.
– If processes are changed, then the SOP
needs to be updated.
Standard Operating Procedures
• After an SOP is approved
– All applicable personnel need to be trained on
the SOP.
– Training may be done by:
• Self-training
• In-service
• Hands-on training
– All training needs to be documented.
Standard Operating Procedures
• Non-compliance issues
– Can’t find it!
– Can’t understand it!
– Can’t follow it!
– It’s confusing!
– That’s how we used to do it!
– My way is better!
– Who cares anyway!
– Who has the time!
Quality Assurance
• What is it?
– A comprehensive review of key aspects of a
process to assess compliance with standards
and systems.
– Inspection system that checks inputs and
outputs.
– A planned and systematic activity
– Usually retrospective and sample-based
Quality Assurance
• Is QA the same as QC?
– Quality Control is:
• Usually a 100% review
• Usually data driven
• Usually done in real time
Quality Assurance
• Why do QA?
– Provides assurance that the protocol, SOPs,
and GCP are being followed.
– Ensures the site is ready for an audit.
– Ensures that data generated are valid and
verifiable.
– Ensures that processes are effective and if
not can help to streamline them.
– Data can be used for business development
or recruitment.
Quality Assurance
• The final result:
Quality Assurance
“Quality cuts out repetition and slices off
delays.”
Monitoring
• Definition:
– The act of overseeing the progress of a
clinical trail, and of ensuring that it is
conducted, recorded, and reported in
accordance with the protocol, standard
operating procedures, GCP and the
applicable regulatory requirements.
ICH GCP E6 Document
Monitoring
• The sponsor shall monitor the progress of
all clinical investigations being conducted
under its IND.
21 CFR 312 Sec 312.56
Monitoring
• Purpose:
– To verify that
• The rights and well-being of human subjects are
protected.
• The reported trial data are accurate, complete, and
verifiable from source documents.
• The conduct of the trial is in compliance with the
currently approved protocol/amendments, with
GCP, and with applicable regulatory requirements.
Monitoring
• Qualifications of monitors:
– Appointed by the sponsor
– Appropriately trained with the scientific and/or
clinical knowledge needed.
– Thoroughly familiar with the investigational
product, the protocol, written informed
consent form and any other written
information to be provided to subjects, the
sponsor’s SOPs, GCP, and regulatory
requirements.
Monitoring
• The extent of monitoring of the trial is
based on its:
– Objective
– Purpose
– Design
– Complexity
– Blinding
– Size
– Endpoints
Monitor’s Responsibilities
• Monitor’s Responsibilities
– Main line of communication between the
sponsor and the investigator
– Verify that the investigator has adequate
qualifications and resources.
– Verify that the staff and facilities are adequate
to safely and properly conduct the trial.
– Verify drug accountability
– Verify that the protocol is followed
Monitor’s Responsibilities
• Verify that IRB consent is obtained for protocol
and then for any amendments.
• Verify that informed consent was obtained for
each subject
• Ensure that investigator receives current IB,
documents, and supplies
• Ensure that the investigator and staff are
adequately informed about the trial
• Verify that trial functions are performed as per
the protocol
Monitor’s Responsibilities
• Verify that only eligible subjects are
enrolled
• Report the recruitment rate
• Verify source data/documents and other
trial records
• Verify that the investigator provides all
required reports, notifications,
applications, and submissions.
Monitor’s Responsibilities
• Check the accuracy and completeness of the
CRF entries, source documents, and trial
records against each other.
– Data required by the protocol are reported accurately
on the CRFs and that they are consistent with the
source data/documents.
– Any dose &/or therapy modifications are documented
– AEs, con meds, & intercurrent illnesses are reported
– Missed visits, tests, & examinations are clearly
reported
– Withdrawals/dropouts are reported and explained on
the CRFs
Monitor’s Responsibilities
• Inform the investigator of any CRF errors,
omissions, or illegibility.
• Determine whether all AEs are reported within
the time periods required by GCP, protocol, IRB,
sponsor, and regulatory requirements.
• Communicate deviations from the protocol,
SOPs, GCP, or regulatory requirements to the
investigator and take appropriate action to
prevent recurrence.
Monitoring Report
• A written report should be submitted after
each visit or trial-related communication
• Report should include a summary of what
the monitor reviewed and any significant
findings, deviations, deficiencies,
conclusions, actions taken or to be taken.
Monitoring
• Monitor visits are usually divided into:
– Pre-study visit/site selection visit
– Study initiation visit
– Monitoring visit
– Study close-out visit
• Telephone communications
Monitor Visits
• Pre-study Visit/Site Selection visit
– Assess the suitability of a site to meet the
requirements of a study
•
•
•
•
•
•
Investigator issues
Study conduct
Review of potential subject population
Staff
Institutional relationships
Facilities and equipment
Monitor Visits
• Study Initiation Visit
– Review protocol, informed consent, & CRF in
detail with entire staff involved in study
– Review procedures for study drug dispensing,
accountability, and storage
– Ensure adequate training has been completed
Monitor Visits
• Study Initiation Visit
– Ensure adequate supplies of clinical trail
materials and equipment
– Review lab schedule and normal ranges
– Review AE reporting procedures
– Review contents of the investigator file
– Review monitoring schedule and procedures
Monitor Visits
• Study Initiation Visit
– Review the QA procedures of site
– Discuss likely start date
– Communicate sponsor standards
– Communicate regulatory requirements/GCPs
Monitor Visits
• Monitoring visit
– Check that the facilities/equipment are still
adequate
– Review any staff changes
– CRF review
– Current status of study
– Withdrawn patients
– AE review
– Protocol followed
Monitor Visits
• Monitoring visit
– Informed consent documentation
– Drug accountability
– Lab procedures and review abnormal values
– Adequate supplies
– Review any other problems
– Ensure investigator’s file is up to date
Monitor Visits
• Study Close-out Visit
– Review/collect remaining CRFs
– Verify/collect outstanding edits from prior visits
– Accountability and return of study drug & clinical
supplies
– Ensure study files are complete
– Ensure proper secure storage/retention of records
– Review investigator reporting/study responsibilities
– Final payment and administrative matters
Questions?
care
community
research
teach
Compliance and Audit
Fraud
• The fabrication or falsification of data or
any component of a research trial
constitutes fraud and is unquestionably
characterized as research misconduct.
• Completion of a study in a way that
compromises the validity or reliability of
the findings or violates the rights of the
subjects.
Fraud
• Research Misconduct
– Falsification of data in proposing, designing,
performing, recording, supervising, or
reviewing research, or in reporting research
results
– Includes acts of omission and commission
Fraud
• Acts of omission
– Deliberately withholding information
• E.g. Adverse events, con meds
• Acts of commission
– Falsification of data
– Inventing data
• E.g. Lab values, BP readings
Fraud
• Deliberate or repeated noncompliance
with the regulations are considered
misconduct
Fraud
• What is not fraud?
– It does not include honest error or honest
differences of opinion.
– Lies told by patients/subjects
5 Elements of Fraud
•
•
•
•
Evidence of false presentation of data
Prior knowledge that the data was false.
Individual promoted the false data claims.
Sponsor and/or FDA believed the data to
be true within reason.
• Damage occurred as a result of the data
or factual account of the clinical trial.
Fraud
• What are the consequences of fraud??
– Places all subjects in that trial at possible
safety risk
– Jeopardizes the reliability of clinical trial data
– Breach of medical and scientific ethics
Fraud
• Data falsification
– Physical or lab exams
– Biological specimens
– Subject Identities
– Drug compliance records
– Sample collection times
• These are just a few examples!
Fraud
• Why is data falsified?
– To qualify ineligible subjects
– To please the bosses by filling in the blanks
and making the source documents match the
CRF
– For fun
– For profit
– Pressure on the investigator to publish
Fraud
• How can we prevent fraud?
– Ensure that staff have necessary resources and
support to follow the protocol and complete the trial
– Educate staff on protocol, study drug, and CRFs
– Avoid unreasonable demands on site
– Ensure adequate education of staff on GCP
– Develop and implement SOPs
– Internal monitoring/QA to ensure compliance with
regulations and guidelines
Fraud
• Everyone is responsible for reporting
fraud.
Therefore,
• Everyone should be on the lookout for
signs of fraud.
Fraud
• Education is the key to improving trial
quality.
• Education must target all who participate
in clinical trials.
• Education must be a continuous process.
Notable Example of Fraud
• Fiddes, 1999
– President of a Clinical Research Co. in
California during 1990’s
– Participated as an investigator in over 200
trials.
– Involved in 91 submissions with 47 different
sponsors.
Notable Example of Fraud
• Engaged in extensive fabrication and
falsification of data.
• Purchase bacteria from supplier and sent to labs
as samples from patients ears.
• Used one patients urine and submitted for
several other patients.
• Used family members as manufactured research
subjects
• No one suspected him because he was such a
well respected investigator.
Notable Example of Fraud
• Several coordinators reported this to
monitor who in turn reported to the
Sponsor.
• When questioned by the sponsor, Fiddes
response was one of outrage and
requested that a new monitor be assigned.
• Had it not been for a disgruntled
employee, Fiddes would still be operating.
FDA Inspections
• FDA Bioresearch Monitoring Program
– Performs site visits to clinical investigators,
research sponsors, CROs, IRBs, and
nonclinical (animal) laboratories
– Designed to monitor all aspects of the
conduct and reporting of FDA regulated
research
– Objective of all inspections is to ensure the
quality and integrity of data and information
submitted to FDA as well as the protection of
human research subjects.
FDA Inspections
•
Clinical Investigator Inspections
– 3 Types
1. Study-oriented inspections
2. Investigator-oriented inspections
3. Bioequivalence study inspections
FDA Inspections
•
Study-oriented inspections
– Based on studies that are important to
product evaluation
• Pivotal studies for a pending NDA
• Pivotal studies for product license
applications
FDA Inspections
•
Investigator-oriented inspections
–
–
–
–
–
–
May be initiated because an investigator conducted
a pivotal study
May be because the sponsor has reported to the
FDA that they are having difficulty getting reports
from the investigator or that they have a concern
about their work
May be based on a subjects complaints
May be because they have participated in a large
number of studies or have done work outside their
specialty area
Inconsistent safety or effectiveness findings
Too many subjects with a specific disease given the
locale of the investigation
FDA Inspections
• Bioequivalence study inspections
– Conducted because one study may be the
sole basis for a drug’s marketing approval
– Requires participation by an FDA chemist or
an investigator knowledgeable about
analytical evaluations
FDA Inspections
• Inspection Procedures
– FDA investigator from district office will
contact investigator to arrange a time for the
visit.
– At visit, he will show FDA credentials and
present a “Notice of Inspection” form
FDA Inspections
•
Investigation consists of 2 basic parts
1. Determining the facts surrounding the conduct of
the study
– Who did what
– Delegation of authority
– Where was the study done
– How/where the data were recorded
– Study drug accountability
– How the monitor communicated and evaluated
the study’s progress
FDA Inspections
•
Investigation consists of 2 basic parts
2. Study data is audited
– FDA compares the data submitted to the Agency
with all available records that might support the
data.
What will FDA Inspect?
• Randomly selected
files
• 100% of informed
consent
• All serious and
unexpected AEs
• Regulatory Binder
• 100% of
investigational drug
inventory
• Source documents
vs. CRFs
How Thorough is the Inspection?
• Expect the FDA
Not to Miss
ANYTHING!
• Expect the FDA to
Document
EVERYTHING!
FDA Inspections
• After the inspection, the FDA issues its
inspection findings.
– Conduct an exit interview
• Discuss findings
• Clarify any misunderstandings
• May issues a form FDA-483 (Inspectional
Observations)
FDA Inspections
• After the inspection, the FDA issues its
inspection findings.
– FDA issues a letter to the investigator
• 3 types
– No Action Indicated (NAI)
– Voluntary Action Indicated (VAI)
– Official Action Indicated (OAI)
– In cases of serious deviations, the FDA may
take other courses of action such as
regulatory or administrative sanctions.
FDA Inspections
http://www.fda.gov/cder/present/dia-62000/woolen1/sld007.htm
FDA Inspections
http://www.fda.gov/cder/present/dia-62000/woolen1/sld008.htm
FDA Inspections
• What does the FDA look for:
– Source of study subjects
– Inclusion/exclusion criteria
– Was the protocol followed
– Adverse events
– Adequacy of reports
– Informed consent
– IRB review obtained
– CRFs completed
FDA Inspections
• What does the FDA look for:
– Comparison of source data to CRFs to data submitted
to FDA
• Look for adequate documentation to assure that all subject
exist
• Look for any comments in the raw data not reported on the
CRF
• Look for subjective comments such as patient complains
• Look for concomitant prohibited medications that unrecorded
protocol deviations.
FDA Inspections
• What does the FDA look for:
– Dropouts
– Who else was involved in the study
– IRB correspondence
– SOPs
Preparation for an Inspection
• Best preparation is before an investigation is
even announced!
– Training programs for all staff including investigators!
•
•
•
•
GCP
Regulatory requirements
Job responsibilities
SOPs
– Organization and maintenance of regulatory
documents
Preparation for an Inspection
• Gather required documents
–
–
–
–
–
–
–
–
–
–
–
Signed protocol/amendments
Signed FDA form 1572 and accompanying CVs
IB
IRB documentation
Informed consents
CRFs
Source documents
Study drug accountability records
SAE reports
Site visit log
Subject master list
Preparation for an Inspection
• Notify PI, sponsor or sponsor designee, IRB in
the event of an FDA, OHRP or NIH inspection
• Assure that all records are available for
inspection.
• Selection of a “point person” This person should
be available through-out the inspection.
• Identify an uncluttered room for the Inspector to
review records.
At The Inspection
•
•
•
•
•
•
•
Stay calm
Give clear, concise answers to questions asked
Do not volunteer additional information
Do not speculate
Accompany the FDA investigator at all times
Have staff available who participated in study
Keep an additional copy of each copy that you
give to the FDA investigator.
• A general inspection log should be kept for each
day of the inspection.
At The Inspection
• Know your job responsibilities
• If you don’t understand the question, ask
for a clarification
• Answer truthfully
• If you don’t know the answer, say so
• Refer to documentation if you need to
• Do not argue
care
community
Challenges in
Recruitment
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Current Environment
• Patient recruitment and retention is the
leading bottleneck in studies today
• Patient recruitment occupies 27% of the
cost of clinical development.
– $5.3billion globally
• 1 in 20 recruited patients provides data
that can be used in the regulatory dossier.
• >75% of all trials fail to meet their
recruitment deadlines.
Current Environment
• Missed deadlines
– Phase I last 42% longer
– Phase II last 31% longer
– Phase III last 30% longer
• Of 612 Investigative sites, 45% rate
patient recruitment as source of delay
Options
• Direct to patient advertising
– Television – special interest stories
– Radio
– Newspaper
– Posters in the clinic
• Physician practices
• Centralized recruitment
Media Can Work
•
•
•
•
Right vehicle
Right patient demography
Repetition
Targeted strategies to infuse small
markets.
Advertising
• IRB Approval
• Include:
– the name and address of the clinical
investigator and/or research facility
– the condition under study and/or the purpose
of the research
– Enrollment criteria
– Benefits
– Contact info
191
Wording
• State if investigational drug
• Do not promote “free medical care”
• Do not emphasize payment
192
Recruitment Script
• IRB reviews process
• IRB reviews info to be collected for
database
• IRB reviews script
193
Employ Marketing Strategies
•
•
•
•
•
Product = Protocol design
Price = Patient’s benefit of participation
Place = Investigator’s site
Patient needs to be the focus.
Message must target the patient
population.
Common Mistakes in Recruitment
• Failure to consider patient population or
physician patient relationship in designing
the campaign
• The site’s capacity
• Poorly considered media and recruitment
tactics
• Failure to forecast, report and redeploy
Cost of Not Meeting Enrollment
• $600,000-$8M in lost revenue for every
day a drug is delayed to market.
Patient Recruitment Advertising
and Marketing Tools
Flyer
2.4
2.6
Health fair
2.7
2.9
Internet/Websites
2.9
3
TV
3.1
3.5
Physician referral
3.9
0
0.5
1
1.5
2
2.5
3
3.5
Patient Recruitment Impact Ratings
4
4.5
Sources of Patients for Studies
• Referrals: patients from within practice or
from another practice.
• Direct mailings
• Health screenings
• Web – becoming increasingly popular
• Newspaper advertising
• Radio and television advertising
Making Physician Referrals Work
•
•
•
•
Dear Dr letters with a new look
Coordinator to Coordinator
Community networking
Presence in the physician’s office during
office hours.
Protocol Design and Patient
Recruitment
• Any protocol design should first be based
on good science
• There can be statistical advantages to
selecting a narrowly defined patient
population
• There are disadvantages also:
DIFFICULT TO RECRUIT!
Elements of a Protocol Which
Impact Recruitment
• Length of study: longer studies are harder to recruit and
also to retain.
• Choice of control group: Placebo controlled often are
more difficult to recruit for.
• Inclusion Exclusion Criteria: new onset Rheumatoid
Arthritis (RA) with no use of steroids would be harder to
find than RA symptoms for less than 2 years.
• Degree of Disease: Advanced RA vs. mild RA
• Concomitant Disease: MI with no hx of HTN vs MI alone
• Medication exclusions: patient with CHF who are not on
an ace inhibitor.
• Procedures performed: 3 extremity x-rays and 3 MRIs
would be a challenge for someone’s schedule.
Elements of a Protocol Which
Impact Recruitment
•
•
•
•
Blood draws
Invasive diagnostic procedures: tumor staging
Biopsies: skin biopsy to dx a derm disorder.
Medication withdrawal. Taking someone off of
their anti-hypertensive.
• Availability of open label extension study always
enhances subjects because it means if the drug
is working they can continue it.
Patient Recruitment
• Need to focus significant resources on
recruitment outside the medical practice
– Nearly 2/3 or al enrolling patients are self referred.
• Part-time sites account for nearly 40% of all
study conduct dollars and these sites do not the
money for full time recruiters or SMOs
– Professional recruitment groups structure entire
recruitment campaigns, including the design and
placement of advertising and follow-up. They often
have patient databases.
Patient Databases
• Recent under scrutiny because of HIPAA
• Databases are often vague and can not identify patients
with osteoarthritis vs rheumatoid arthritis.
• Database should be able to select pre-qualified
volunteers given specific set of criteria
• Should not be the sole source of patient recruitment.
• Contracts hneed to be created to determine to whom the
database belongs.
• Subjects being pre-screened for studies should be
advised of what will be done with this confidential
information that they are providing.
Role of a Call Center
•
•
•
•
•
•
Patient recruitment
Site referral
Appointments
Retention
Compliance
Adverse events
Recruiting Patients on the Internet
• 1999 less than 15% clinical research
professionals using the internet for patient
recruitment.
• By 2001 almost 50% use the internet for
recruitment.
Using the Internet
• Need to have good online and offline
targets.
– Advertise website
– Good presence on search engine
Registering Trial
• Must be registered at
www.clinicaltrials.gov
• Generally done by sponsor
• Check anyway!
208
Other Academic Institutions
•
•
•
•
•
Harvard: No central recruitment
Mayo Clinic
University of Wisconsin
UCLA
FCCC
Other Resources
Clinicaltrials
Biotrax
Subject Retention
• Retention is result of various factors that are all
directly linked to the human interaction between
the site and the potential patient
• Retention is directly linked to patient satisfaction.
• Recruitment
– Precursor to patient retention
– Advertising that is simple, direct and no n-coercive
• Informed consent that provides sufficient and
understandable information without being so
lengthy and highly technical that the patient is
too intimidated to sign it. Staff presenting should
be caring and willing to answer questions.
Possible Predictors of People
predisposed to Drop Out of a Study
•
•
•
•
•
Lower income
Lower education level
Unstable or high risk phycial status
Low levels of social support
An ethnic or socio-economic status
different from that of the investigator
Retention
• Drop-out rates vary widely, but range from 15%
to 40%, with even higher rates reported.
• Reasons for patient dropout from a year-long
asthma study
–
–
–
–
–
–
–
Tx non compliance
Tx adverse event
Tx lack of benefit
Other medical condition
Moved from area
Administrative termination
Other resons
17%
17%
12%
11%
4%
22%
17%
Subject Compensation: What is
Reasonable?
•
•
•
•
How much is the patient inconvenienced?
Is the patient hospitalized?
How much travel time is involved?
How many additional procedures are
required for the study?
• How invasive are the procedures?
• Cost of living
care
community
GCP at Investigator Site
Donna W. Dorozinsky, RN, MSN, CCRC
research
teach
Recruitment
• All advertising materials must be IRB
approved.
• Any documents given to the subject or
seen by the subject must be IRB
approved.
• All scripts must have IRB approval
• Inability to meet recruitment is #1 cause in
delays of study completion
Elements of a Protocol Which Impact
Recruitment
• Length of study: longer studies are harder to recruit and also to
retain.
• Choice of control group: Placebo controlled often are more
difficult to recruit for.
• Inclusion Exclusion Criteria: new onset Rheumatoid Arthritis
(RA) with no use of steroids would be harder to find than RA
symptoms for less than 2 years.
• Degree of Disease: Advanced RA vs. mild RA
• Concomitant Disease: MI with no hx of HTN vs MI alone
• Medication exclusions: patient with CHF who are not on an ace
inhibitor.
• Procedures performed: 3 extremity x-rays and 3 MRIs would be
a challenge for someone’s schedule.
Elements of a Protocol Which Impact
Recruitment
•
•
•
•
Blood draws
Invasive diagnostic procedures: tumor staging
Biopsies: skin biopsy to dx a derm disorder.
Medication withdrawal. Taking someone off of their
anti-hypertensive.
• Availability of open label extension study always
enhances subjects because it means if the drug is
working they can continue it.
Informed Consent Process
Includes:
• Clear discussion of the information in the
ICF.
• Signed and dated ICF.
• Copy of signed ICF to subject.
• Documentation of time and date that
consent process was conducted.
Informed Consent
• Obtained “prior to” participation in a clinical
study.
• Includes any specific exams or procedures
specific to the study (hts, wts, VS, ECGs)
• Before discontinuing any existing
medications the subject is taking for the
purpose of determining suitability for the
study.
Informed Consent
• If new information becomes available that may be
relevant to the participant’s continued participation,
communication of this information must be
documented.
• Updated/amended ICF should be explained and
signed by both the consenter and the participant.
• A copy of signed new consent will be provided.
Informed Consent
• According to FDA’s Information sheets, the FDA does
not require reconsenting of subjects that have
completed their active participation or of subjects
actively participating when the change will not affect
their participation (ex. future cohorts affected).
• Must reconsent only if they are directly affected (ex.
increased drug mutagenecity)
Source Documentation
• Importance of Documentation
– Necessary for the reconstruction, evaluation,
and validation of clinical findings,
observations, and other activities during a
clinical trial –ICH 1.52
– Substantiates the integrity of trial data,
confirm observations that are recorded and
confirm the existence of subjects.
Source Documentation
• Purpose:
– To record a subject’s history, diagnosis, and
medical management
– Enable monitors to verify that trial data are
accurate, complete, and verifiable
– Permit a reconstruction of the trial
Source Documentation
• Apply ALCOA to achieve data quality
– Attributable
– Legible
– Contemporaneous
– Original
– Accurate
Source Documentation
• Source documents should be the original document. If
a copy is used as a source document, it should be
certified that it was verified to be an exact copy of the
original, having all of the same attributes and
information as the original.
• If the original document is retained elsewhere in the
study file, the copy does not need to be certified.
Source Documentation
• Must have:
– Subject number or identifier
– Date/time of collected data point
– Data
– Signature of person making observation
• Unless data is automated (e.g. Dinamapp printout)
Recording of Source Data
• Must be permanent
– Black ink or typed
• Protected from unauthorized change
– Nothing that can be erased
• Sequence should be chronological
• If additions need to be made, they need to
be signed and dated.
• Original entry must be visible if corrections
are done. (audit trail)
Recording of Source Data
• Corrections should be made according to
GCP
– Draw a single line through data to be
corrected, record new data, initial and date
correction.
• If reason for change is not obvious, it
should be explained.
• If data are transcribed (e.g. lab data), the
source data is the original laboratory
report.
Recording of Source Data
• When a subject drops out of a study
– Document the reason for dropping out
– Keep a record of attempted and actual patient
contacts
– Obtain all follow-up information where
possible
– If unable to obtain follow-up, document the
subject as lost to follow-up.
Electronic Source Data
• If there is electronic data as well as
printouts, the electronic data is defined as
the source data.
– This will decrease the risk of the data files
being changed but the printout remaining
unchanged.
Source Documentation Do’s
and Don’ts
• Do’s:
– Do print legibly.
– Do use a black ballpoint pen.
– Do make sure your letters and numbers are legible and easy
to read.
– Do complete all sections of each page as requested.
– Always use a 24 hour clock.
– Dates should be recorded in the day, month, year format
(dd/mmm/yyyy).
Source Documentation Do’s
and Don’ts
• Do’s
– Checkboxes should be marked with a
checkmark or an X
– Do use only accepted medical abbreviations.
Source Documentation Do’s
and Don’ts
• Don'ts
– Don’t add information at a later date without indicating that
you did so.
– Don’t date the entry so that it appears to have been written at
an earlier time.
– Don’t add inaccurate information.
– Don’t destroy original documents even if they require error
correction.
– Don’t alter information.
Safety Monitoring
• Values of Potential Clinical Concern
– Determined by the physician
– Labs
– ECGs
– Diagnostic findings
– Clinical Significance – Adverse Events
Adverse Events
•
•
•
•
•
•
Monitor at each visit
Follow-up on open AEs
Continuing at end of study
Protocol defined adverse events
In early development report everything
Open ended questions “how do you feel?”
Adverse Events
• Assignment of Causality
• Severity – as observed as well as reported
• Include an assessment of what you see,
contributes to assignment of causality
• Medical terminology
• Mapping of terms
• Consistency in CRF completion
Protocol Adherence
• Protocol Deviation
• An incident involving noncompliance with the
protocol but does not affect the subject’s rights,
safety, welfare, or the integrity of the resultant
data.
• Protocol Violation
• More serious, may involve critical study
parameters.
• May render a subject ineligible
• Affects the subject rights, safety, welfare or data
integrity.
Reporting
• Deviations
– Document any discussions between sponsor
and investigator
– Submit as a summary to the IRB at time of
continuing review
• Violations
– Report to IRB immediately
•
•
•
•
Description of event
Note any compromise to patient safety
Documentation of communication with sponsor
Corrective action plan
Site Management
• Defined process for handling
violations/deviations
– Define responsibilities
– SOP vs protocol
•
•
•
•
Root cause analysis
Communicate to all parties
Track trends
Corrective actions
Drug Accountability
• Control of investigational drugs, vaccines, or devices (article)
– To provide accountability system to address receipt, distribution,
and return of all investigational supplies
– To ensure that supplies are properly stored and accessible only to
designated study staff
– To ensure that investigational materials are used only according to
protocol
• All Clinical Trial Materials (CTM’s) must be accounted for and
disposed of per protocol. Pharmacy accounts for all drugs given,
returned or destroyed, but investigator retains legal accountability
for this.
What does GCP mean to me?
• Must have
– Adequate documented training of staff
– Data handling systems and procedures
• SOPs!!!
– Quality Control Processes
– Computerized systems standards
– Maintenance of Audit trails
?????
• Evaluations
• Post Test for CEUs