Challenges

1
Challenges Considerations When Running a
Clinical Studyand Surviving the FDA Audit

• Sharon Timberlake, CCRA, RAC
• Palomar Medical Technologies, Inc.
• Director, Clinical Regulatory Affairs

2
Outline

• Challenges Considerations-Running a Clinical
  Trial
• Selecting the Right Investigational team
• Overcoming common delays
• Surviving the FDA Audit
• When do they audit
• Helpful tips
• The typical Inspection
• Audit results effect on your company
• Warning letter examples

3
Selecting the Right Investigational Team

• Create Your Checklist of the Perfect Site
• Experience with clinical studies
• Background with similar technology
• Knowledgeable with condition to treat
• Interviewing Potential Sites
• Set up to follow the protocol
• Appropriate test equipment
• Adequate staffing
• Diverse demographics
• Be Selective

4
Selecting the Right Investigational Team-Cont.

• Choosing the Lead Investigator
• One recognized physician
• Dont select too many big names
• Someone who will be compliant
• May not be the highest enroller
• Choosing the Other Investigators
• Young investigator trying to make a name
• Highest enrollers
• Interested in the science
• Willing to spend time on the study

5
Common Delays

• Sponsor Delays
• Protocol agreement
• FDA review of protocol
• Device issues/availability
• Staffing issues
• Budget delays
• Site Delays
• Slow enrollment
• Site issues
• IRB submission
• Contract Sign-off

6
Summary

• Be selective
• Choose your sites wisely
• Due diligence
• Expect delays that are out of your control
• Prepare early for issues that are within your
  control

7

• SURVIVING THE FDA AUDIT

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When do they audit?

• For Cause
• Routine Audit
• Pending 510(k) Application
• Pending PMA Application
• Select Several Clinical Sites
• Highest enrollers
• Suspicious data
• Number of studies at a site
• Too clean

9
Helpful Tips

• Dont panic
• Inform all sites of potential audit
• Send company staff for pre-audit of site(s)
• Review/organize as necessary
• Dont change any data
• Dont generate new data queries
• Review potential issues
• Complete any missing holes

10
Helpful Tips Continued

• Notify the Institutional Review Board
• Staff understands protocol and amendments
• Staff availability/responsibility during audit
• Review subject charts for completeness
• Informed consents on file
• Placement of auditor during visit

11
The Typical Inspection

• Inspectors typically review
• Documentation to applicable CFR
  www.fda.gov/ora/ftparea/compliance/48_811.pdf
• Properly executed consents/revisions
• IRB approvals, annual reports, and correspondence
• Adverse device effects
• Monitoring reports
• Data verification (source, CRFs, and submitted
  to FDA)
• Protocols and amendments
• Device accountability records
• Sponsor correspondence

12
How Audits Effect Your Company

• No observations or minimal findings-agency
  continues review of marketing application
• Application not accepted
• Withdraw data from application
• Enroll new subjects
• Company timeline delays
• Affects your reputation with the FDA
• Investor reactions

13
Clinical Investigators

• Recent Warning Letters

14
3/2/04 University of Chicago

• You implanted significant risk devices that did
  not have an FDA approved IDEor PMA application
• Implanted device in 8 subjects over 6 weeks
• Violation-use of an adulterated under section
  510(f)(1)(a) of the Act, prohibited act under
  section 301(c) of the Act
• Corrective Action-notify all subjects via
  certified mail, emergency contact information,
  FDA may review medical records, provide list of
  all subjects that received implant-including DOB,
  date and reason for surgery, notify IRB

15
6/18/03 Brigham Womens

• Failure to obtain informed consent
• 21 CFR 50 and 21 CRF section 812.100
• Failed to obtain from 2 subjects prior to
  treatment (consented after treatment)
• 1 subject signed an outdated consent

16
Brigham Continued

• Failure to conduct the study in accordance with
  the investigational plan
• 21 CFR 812.100 and 21 CFR 812.110(b)
• Study procedures used to evaluate safety and
  efficacy of the device were not performed or not
  within the timeframes of protocol
• 11 subjects did not have baseline laboratory
  testing
• 5 subjects were not assessed by telephone
• Subjects not seen within the scheduled follow-up
  period

17
Brigham - continued

• Failed to fulfill device control responsibilities
  under the investigational plan
• Devices not maintained under controlled access
  storage
• Devices received by hospital staff not part of
  the clinical investigation
• Devices handled by others before they were
  inventoried by study staff
• Hospital personnel had keys to storage area
• Devices received from sponsor were not completely
  accounted for logged in correctly

18
Brigham - Continued

• Failed to prepare and maintain accurate,
  complete, and current records relating to the
  receipt, use, and disposition of the
  investigational devices
• Failed to prepare and maintain accurate,
  complete, and current device accountability
  records, as required by 21 CFR 812.140(a)(2)
• Records of devices returned to sponsor contained
  inaccurate information regarding lot numbers and
  quantities

19
10/27/03-Stimsoft, Inc.

• Failure to ensure proper monitoring of the
  investigation
• 21 CFR 812.2(b)(1)(iv)
• 21 CFR 812.40
• 21 CFR 812.46
• Failure to promptly secure compliance from or
  terminate participation by a non-compliant
  investigator
• 21 CFR 812.2(b)(1)(iv)
• 21 CFR 812.46(a)

20
10/27/03-Stimsoft, Inc.-Cont.

• Failure to ensure that clinical investigators
  obtain and document informed consent and maintain
  records relating to the clinical investigation
• 21 CFR 812.2(b)(1)(???)
• 21 CFR 812.2(b)(1)(v?)
• Failure to prepare and submit required reports
• 21 CFR 812.150(b)
• 21 CFR 812.2(b)(1)(v)
• Failure to keep records on investigator financial
  disclosure
• 21 CFR 814.20(b)(12), 21 CFR 54.6

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Summary

• Conduct study according to protocol
• Monitor sites frequently
• Work closely with sites-team approach
• Support the sites during an audit

22
Final Thoughts

• Plan Carefully
• Ease of protocol
• Rational timelines
• Choose experienced Investigators
• Educate sites on applicable regulations
• Visit/monitor clinical sites frequently
• Listen to the sites and your staff

23
Thank You!

• Sharon Timberlake, CCRA, RAC
• Palomar Medical Technologies, Inc.
• Director, Clinical Regulatory Affairs
• stimberlake_at_palmed.com