Good Clinical Practice and Audit Preparedness

1
Good Clinical Practice and Audit Preparedness

• IUPU Symposium - October 2010

Michael R. Hamrell, Ph.D. MORIAH Consultants
2
What is Clinical Research?

• The essential piece to demonstrate that a new
  product is safe and effective
• The most costly part of development
• 60 of cost spent on clinical
• The most time-consuming part of product
  development

3
Quality Concepts in Clinical Trials

• Sponsor Responsibilities
• Ensure proper monitoring of investigations (21
  CFR 312.50)
• Monitor the progress of all clinical
  investigations being conducted under its IND (21
  CFR 312.56(a))
• Correct and/or report serious non-compliance to
  the FDA (812.46(a))

4
Quality Concepts in Clinical Trials

• Clinical Investigator Responsibilities
• Conduct study according to the protocol
  (21 CFR 312.60 812.100)
• Maintain adequate and accurate case histories (21
  CFR 312.62(b) 812.140)

5
Role of the Coordinator

• Clinical Research Coordinator (CRC)
• Works under the direction of the Principal
  Investigator
• Expected to perform many of the tasks in the
  clinical study
• need to be qualified (and trained) to perform the
  task
• PI still responsible for all patients

6
Role of the Coordinator

• Often is the key person for the successful
  conduct of a trial
• Typically has the most patient contact and direct
  role in many key tasks
• Usually the person who fills out the CRFs, lab
  slips, etc.
• Tasks will depend on professional qualifications
  and training

7
Safety Reports

• Investigator is required to report all adverse
  events to Sponsor
• timing depends on nature and severity
• has major impact on subject safety

21 CFR 312.64(b) 812.150
8
Quality Concepts in Clinical Trials

• IRB Responsibilities
• Organization and Personnel through review of IRB
  membership list (21 CFR 56.107)
• Functions and Operations through evidence of
  written SOPs (21 CFR 56.108)
• Review of Research through sufficient details of
  IRB meeting minutes (21 CFR 56.109)

9
Product Accountability

• Focus on complete picture
• Shipping
• Receipt
• Use
• Returns
• Reconciliation

10
Product Accountability
4
Test Articles Reconciled By Sponsor
Investigator Timepoint A
Investigator Timepoint B
Patient
11
Test Article FDA Comment

• Although the sites personnel have been
  delegated the responsibility for test article
  accountability, it is the Principal Investigator
  who is ultimately responsible for the this task.
• Even when a research pharmacist is involved in a
  study at a site, the clinical investigator
  retains responsibility for ensuring that the test
  article was appropriately prepared, dispensed and
  administered.

12
FDA Viewpoint on Auditing

• FDA takes no official position on whether
  companies should conduct clinical audits
• FDA viewpoint on sponsor responsibilities
  Sponsors are responsible for selecting qualified
  investigators ensuring that the investigation(s)
  is conducted in accordance with the general
  investigational plan and protocols contained in
  the IND 21 CFR 312.50 812.40

13
Whats the Chance of an Audit

• According to the Inspector Generals Report on
  The FDA Oversight of Clinical Trials (Sept
  2007)
• FDA only inspects less than 1 of all clinical
  trial sites
• 75 of inspections overall were routine
  (surveillance)

http//oig.hhhs.gov/oei/reports/oei-01-06-00160.pd
f
14
How would you characterize your site?

• How would you characterize the staff
• What is the commitment/focus to research relative
  to medical practice
• How is their research performance perceived?

15
Some fun examples
16
Reality Check

• How many of you do multiple clinical trials each
  year?
• Investigator initiated vs. sponsor
• How many of your sites/groups have SOPs?
• How many of your sites use electronic medical
  records?
• How many of you have experience with eCRFs?
• How do you communicate with your IRB (paper or
  electronic)?

17
Should a Site have SOPs?

• Reiterates role of PI in all studies including
  delegation of responsibilities to study staff and
  supervision
• Defines role of PI and staff in study oversight
• Suggests the need for site SOPs

18
The investigator should develop a plan for the
supervision and oversight of the clinical trial
at the site. Supervision and oversight should be
provided even for individuals who are highly
qualified and experienced. A plan might include
the following elements, to the extent they apply
to a particular trial
From Guidance Document
19
ICH GCP Viewpoint

• The auditing of clinical trials is conducted in
  accordance with the Sponsors written procedures
  of what to audit, how to audit, the frequency of
  audits and the form and content of audit
  reports. Section 5.19.3

20
FDA Role in GCP Compliance

• Determine compliance with regulations
• Verify integrity of data

21
FDA GCP Inspections

• FDA will routinely inspect some or all of the
  data for pivotal studies in support of an
  application
• FDA choice of sites are based on a variety of
  factors
• number of sites
• Number of studies at site
• importance of data
• type of study
• Geographic location

22
Role of FDA Inspection

• Essential part of PMA/510K/NDA/BLA review process
• Know your rights
• Use sponsor/CRO/consultants help to prepare
• Build quality into your work

23
FDA Role in Clinical Investigations

• Bioresearch Monitoring Program
• An on-going audit program managed by the Division
  of BIMO in each Center
• To determine the adherence of sponsors, CROs,
  monitors, IRBs and clinical investigators to
  current regulations and official guidelines
• To assess through audit procedures whether data
  submitted to FDA are substantiated by records

24
FDA Inspection of Clinical Research

• FDA Conducts Two Types of Inspections
• Routine data audits (study oriented)
• Audit of key pivotal data from NDAs, BLAs,
  510(k)s, PMAs, etc. to verify data and procedures
• 'For-cause' audits (investigator oriented)
• Targeted audit of data or investigators as a
  result of prior knowledge or suspicion or alleged
  violations of the regulations

25
The Facts About Source Documents

• FDA Requirements Related to source documents in
  clinical trials
• 312.62(b) An investigator is required to prepare
  and maintain adequate and accurate case histories
  that record all observations and other data
  pertinent to the investigations on each
  individual administered the investigational drug
  or employed as a control
• Similar requirement in 812.140 for devices

26
Preparing for the Inspection

• Before you start, make sure you are prepared
• (re)Familiarize with protocol, CRFs, other study
  documents
• Review Study archives
• Check FOI for other inspection results

27
Plan for FDA Inspection

• FDA Arrival
• Who is to be called
• Check FDA inspector credentials
• Accept Notice of Inspection (Form 482)
• Confirm purpose of FDA inspection

28
FDA Form 482
29
Site Policy

• Main Contact
• Identify who is to be notified at the time
  inspection commences and how
• Identify who is authorized to receive and
  accompany FDA inspector
• Plan how oral inquiries and requests for
  documents are processed

30
General Dos and Donts

• DO !
• Greet FDA and ask for identification and FDA Form
  482
• Provide work area that affords privacy
• Make available phone/internet/power
• Offer coffee, tea, water, bathroom
• Provide visitor pass or parking pass
• Keep conversation polite and professional
• Extend common courtesy

31
General Dos and Donts

• Dont even think about !
• Pay for meals
• Offer any monetary compensation
• Offer gifts (even at holiday time)
• Photograph, record or tape things
• Socialize with FDA after work hours
• Ask personal questions
• Look over the inspectors shoulder
• Complain about government, taxes, FDA

32
Company/Site Policy

• Document Production

33
Company/Site Policy

• Document Marking and Duplication
• Do not permit marking of documents by FDA
  Inspector
• Make copies for FDA and retain a copy of each
  document provided to FDA
• Mark documents containing trade secret or
  confidential information before providing
• If confidential information is conveyed orally,
  establish these facts to FDA use witness

34
Company/Site Policy

• Affidavits
• Establish policy on whether to review FDA
  prepared affidavits
• Circumstances under which
• an affidavit could be signed
• Do not sign affidavit or volunteer any
  information unless such disclosure is consistent
  with company policy

35
Plan for FDA Inspection

• During Inspection
• Company/site representative should accompany FDA
  Inspector at all times, to ensure access only to
  information and those parts of the premises under
  the FDC Act

36
Plan for FDA Inspection

• Keep an accurate written record of
• Areas of the site visited and to whom he/she
  spoke
• Accurate and complete record of all comments and
  suggestions made by inspector, unanswered
  questions and site commitments
• Any commitments made to FDA should have
  concurrence of top management

37
Plan for FDA Inspection

• A daily summation with FDA, and separately with
  site staff is helpful
• If additional inspection days are required,
  prepare an agenda for next day with FDA
• Prepare daily report to management

38
Company/Site Policy

• Corrections during Inspection
• If a change is made during the inspection, decide
  whether the change/correction will be conveyed to
  the FDA inspector and, if so, in what manner

39
Correction to 483
40
The Inspection Process
41
What will the Inspectors ask me to produce for
the audit

• Source Documentation
• All of the source documents should cover the
  entire period of the study and be present at the
  time of the audit to allow the auditor(s) to
  properly conduct the audit
• A standard GCP site inspection will include a
  tour of the facility and a thorough review of the
  documentation

42
What will the Inspectors ask me to produce for
the audit

• Documents in the project notebook filed during
  the course of the trial
• List of the study subjects and their
  corresponding study numbers
• Should the FDA investigator ask for the
  identities and demographics of your study
  subjects because of some concern, you are
  required to comply with the request

43
Warning Letter
07-HFD-45-0601
44
What will the Inspectors ask me to produce for
the audit

• Two-way correspondence with the IRB,
  sponsor/monitor
• Original signed consent forms for all the
  patients
• Case Report Forms (CRFs) for all the patients
• Source Documentation (Patient medical records,
  clinic and hospital charts)

45
What will the Inspectors ask me to produce for
the audit

• Records of patients who were study drop outs
• Product storage facilities and accountability
  records
• Serious Adverse Event Reports and documentation
• Monitor visit log

46
Data Inspection Process

• Subject Records
• Did the Investigator maintain records that are
  supportive of each entry in CRFs for each subject
• Were all CRFs completed in a timely fashion

Could you recreate CRF from source?
47
Data Inspection Process

• For eCRF situations
• Were all regulations and requirements followed
  relative to 21 CFR 11
• Do source documents support any
  changes/corrections to the e-CRF

48
Data Inspection Process

• Reporting of Study Progress
• Did investigator terminate or discontinue the
  study before completion
• Incidence and reports of SAEs to Sponsor and IRB
  handled properly
• Did Investigator maintain copies of all reports
  submitted to sponsor and IRB

49
Data Inspection Process

• Records Retention
• Who maintains custody of required records
• Data storage media
• Record storage conditions
• Investigator aware of FDA record retention
  regulations

50
Data Inspection Process

• Data Audit Procedures
• Subject study data
• Number and type of subjects
• Existence and availability of subjects
• Documentation of prior conditions
• Subject inclusion/exclusion criteria
• Screen log/failures

51
Data Inspection Process

• Protocol Adherence
• Enrollment of subjects who did not meet the
  inclusion/exclusion criteria
• Changes in the protocol in dosage, frequency,
  time of dosing, or method of dosing of the test
  article
• Failure to report serious adverse events promptly
  to the IRB and the sponsor

52
Data Inspection Process

• Protocol Adherence
• Failure to document illnesses, hospitalizations,
  and other significant problems concurrent with
  the study
• Failure to perform critical tests, examinations,
  or assessments at the protocol-specific time or
  visit

53
Data Inspection Process

• Protocol Adherence
• Administration of concomitant therapy that could
  compromise the study results
• Failure to report concomitant therapy
• Entering more subjects into the study than
  originally approved by the IRB or the sponsor

54
Data Inspection Process

• Product Accountability
• Did the sponsor maintain accounting procedures
  for the test article
• Were all unused supplies returned to sponsor or
  disposed of properly
• Limitations of test article access and
  distribution
• Route of administration and proper use

55
Data Inspection Process

• Medical/Clinical Laboratory Facilities
• Are the facilities adequate, and proper
  diagnostic equipment available, to fulfill
  protocol requirements?
• Is the equipment in good working order?
• Does the equipment require calibration and are
  there records documenting the required equipment
  calibration?
• Is the laboratory accreditation/license
  documentation current?
• Is there proper documentation and storage of
  trial samples?

56
Data Inspection Process

• Safety Information
• How does sponsor assure that the Investigator
  notifies promptly of SAEs
• Is monitor involved in reporting
• Is timeframe consistent with regulations
• Does source data support SAEs
• Any deaths or dropouts due to SAEs

57
Data Inspection Process

• IRB Communication
• Proper approval and documentation for protocol
  and informed consent
• Documentation of IRB qualifications
• Communication/correspondence between Investigator
  and IRB
• Continuing review performed

58
Its Over Now What??
59
FDA Inspection Follow-up

• At the end of the inspection a discussion is
  scheduled with key personnel to discuss the
  findings (exit interview)
• May issue Form 483
• May note observations (annotate)
• Will record any verbal responses and promised
  corrections

60
What is a 483 Observation?
61
Plan for FDA Inspection

• Exit Interview
• Report of FDA inspector findings with appropriate
  site management
• Opportunity for site to correct any
  misunderstandings incorrect deficiencies
• If Form 483 is issued, each observation should be
  reviewed with the Inspector and understood
• Commitment to FDA
• Plans to correct deficiencies
• Timetable for future actions (answer will be
  recorded by FDA)

62
Plan for FDA Inspection

• After Inspection
• All items on FDA 483 should be responded to in a
  letter to appropriate FDA Office
• Follow-up report to appropriate company/site
  employees

63
Plan for FDA Inspection

• After Inspection
• Form 483 items should be reviewed by company/CRO
  regulatory, technical, or legal personnel
• work with Sponsor to address issues
• State how and when you expect to make corrections
  to FDA

64
Some items can appear in a letter that were not
on the 483
Warning Letter
g4841d
65
What Happens to Inspection Findings?
66
FDA Inspection Follow-up

• FDA Follow-up
• Investigator reviews notes, observations,
  documents collected, etc.
• All records collected during inspection are
  attached as exhibits

67
FDA Inspection Process

• Completion of Inspection
• Inspector returns to office and prepares written
  report of findings an Establishment Inspection
  Report (EIR)
• Audit classification is determined and submitted
  to FDA Headquarters for concurrence

68
FDA Inspection Follow-up

• FDA Follow-up
• A recommendations for classification is made
• Headquarters agrees with Field most of the time
• EIR and exhibits are forwarded to assigning
  office at HQ (BIMO) for final review and
  classification

69
FDA Inspection Process

• Completion of Inspection
• Based on Classification of Inspection follow-up
  letter usually sent
• Additional Courses of Action
• as needed or required

70
FDA Inspection Follow-up

• Follow-Up Letters
• Acknowledgement Letter NAI
• No problems thank you for cooperation
• Information Letter - VAI
• letter may point out deviations from the
  regulations and a written response may or may not
  be requested

71
FDA Inspection Follow-up

• Follow-Up Letters
• Warning Letter - OAI
• Significant deviations from the regulations and
  written response is required within 15 days
• Letter may also include an invitation to an
  informal conference if deviations are major
• may be signal of other regulatory action

72
FDA New Policy on WL

• More rigid internal timelines for issuing 483 and
  follow-up letters
• Send response to 483 within 15 days
• Speedier enforcement following an inspection, if
  needed
• A Warning Letter response can be followed with a
  Closeout Letter, after evaluating the corrective
  action taken, not based on just promised action

73
FDA Inspection Follow-up

• Other Follow-Up Letters
• NIDPOE Letter - Notice of Initiation of
  Disqualification Proceeding and Opportunity to
  Explain
• Most serious deviations from the regulations
  where additional administrative actions are being
  considered
• No further use in studies while under
  investigation

74
BIMO Inspections CompletedFY 2009
Center CI IRB Spon/Mon GLP Total CBER 83
15 11 6 115
CDER 458 102 73 36
669 CDRH 163 79 59 4 305
CFSAN 0 0 0 1 1 CVM
26 na 4 15 45 All
Centers 730 196 147 53 1135
137 BEQ inspections (CDER specific) 1272 total
75
International Inspections - 2009

• Center total
• CBER 3 (2 CI, 1 sponsor)
• CDER 119
• CDRH 12 (10 CI, 2 sponsor)
• CVM 0
• Total 134

76
FY09 CI Inspection Classified All Centers
6
48
46
n 867
77
FY09 Sponsor/Monitor Inspection Classified
All Centers
8
28
64
n 116
78
CDRH BIMO Compliance Rates
2/08
10-Year CDER OAI rate 3-5
79
FY09 IRB Inspections Classified All Centers
7
43
50
n 179
80
Top ten ways to tell your FDA inspection is going
badly

• 10. FDA sets up temporary housing in your parking
  lot
• 9. The FDA inspector mutters uh-oh each time
  he enters a different department, or opens a
  different folder
• 8. A 60 Minutes crew asks to film the
  inspection
• 7. The FDA inspector wont even enter the room
  where the test article is stored
• 6. The Congressman you called for help wont
  return your call, but returns your campaign
  contribution

81
Top ten ways to tell your FDA inspection is going
badly

• 5. Instead of a Form 482, the FDA Inspector
  begins with, You have the right to remain
  silent.
• 4. The FDA inspector comes to audit a specific
  study, but its not one you completed
• 3. The FDA inspector knows all of your
  employees by their first names
• 2. The FDA inspector is a former employee that
  you fired
• 1. The FDA Commissioner conducts the exit
  interview

82
FDAs Purpose for Inspections

• Remember, the FDA is both a Public Health
  Consumer Protection Agency and must assure the
  people that the products it approves meet the
  required standards
• For the government, that means they and you) need
  to AUDIT!

83
Any Questions ?
Michael Hamrell, Ph.D. MORIAH Consultants 714-970-
0790
michael_at_moriahconsultants.com