1. Running a Clinical Trial:
How to Navigate the
Regulatory Maze
Presented by:
Sandra Maddock, RN, BSN, CCRA
President & CEO, IMARC Research, Inc.
We have studied clinical research and regulatory compliance
issues since 1999.

2. In the next hour…
Discuss current FDA climate and the impact
that has on the orthopaedic industry
Identify regulations that govern
clinical research and discuss the
importance of having a solid
regulatory basis for decisions made
in the clinical research setting
Apply regulations to
real-world
scenarios
Sandra Maddock

3. Our Focus: Clinical
Development Design/Prototype
Validation/Verification
Preclinical Testing
Clinical
Regulatory Clearance
Post Market Activities
Sandra Maddock

4. Our Focus: Clinical
Clinical
Research involving human
subjects….
Sandra Maddock

5. Current FDA Climate
• 2009: 510(k) evaluation
– Institute of Medicine Report
– Internal FDA Committee Report
• 2011: FDA releases DRAFT 510 (k) Guidance
– Clinical data required in approximately 10% of
submissions
• New indication for use
• New technology
• Limitations of non-clinical testing methods
Sandra Maddock

6. Current FDA Climate
January, 2012 –
“Device industry watchers say FDA’s new
overarching draft guidance on the 510(k)
pre-market review program introduces new
concepts that may add confusion, not clarity,
to device makers planning to bring new
products to market.”
Sandra Maddock

7. Current FDA Climate
“(FDA changes) could result in
significant disruption to a
program that has served patients
well for more than 30 years.”
Quote from AdvaMed
Sandra Maddock

8. Impact on Orthopaedic Industry
• Stalls innovation
– Unclear processes
• More clinical data required
– 510 (k)
• More scrutiny
– Increase in number of warning letters
– Inspections happening “real-time”
Sandra Maddock

9. Impact on Orthopaedic Industry
FDA Steps Up Scrutiny of Metal Hip
Implants
March 30, 2012
FDA cites orthopedic medical device
company over violations
April 24, 2012
Many medical implants never tested for safety,
Consumer Reports says
April 18, 2012
Sandra Maddock

10. Let’s Shake Things Up
Sandra Maddock

11. “You can fool all of the people some of the time, and
some of the people all of the time, but you cannot
fool all of the people all of the time.”
- Abraham Lincoln
Sandra Maddock

12. You Need To Bring It!
Sandra Maddock

13. What You Need to Know
21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs;
AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR Sponsor CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs;
11; 21
SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812;Good CFR 11; 21 CFR 50; 21 CFR 54; 21
Internal Requirements 21
Clinical
Policies
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;
Practice
21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE
SOPs; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE
SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs;
FDA
SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR
IRB Regulations 50; 21 CFR 54; 21
Requirements
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;
CRO/ Research
21 CFR 50; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE
Monitor Sponsor Site
SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs;
SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;
NIH
21 CFR 50; 21 CFR Guidelines CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE
812; 21 ICH Guidelines
SOPs; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE
SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21 CFR 56; ICH; IRB SOPs;
SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11; 21 CFR 50; 21 CFR 54; 21
Protocol
ISO14155
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS;Requirements
Investigator
PROTOCOL; 21 CFR 812; 21 CFR 11;
21 CFR 50; ICH; IRB SOPs; SPONSOR SOPs; SITE Agreements
SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 21
SPONSOR AND SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;IRB SOPs; It’s Complicated!
Sandra Maddock

14. Adding To The Mix…
Fixed versus
Variable
A decision about regulatory compliance made at one site for
one study may not be the right decision at another site for the
same study or at the same site for another study….
Sandra Maddock

15. Sandra Maddock

16. 21 CFR 812 - IDEs
• 812.110: An investigator shall conduct an investigation in
accordance with the signed agreement with the
Investigator sponsor, the investigational plan, this part and other
applicable FDA regulations, and any conditions of
approval imposed by an IRB or FDA.
• 812.46: (paraphrased) Ensuring compliance with
Sponsor signed agreement, investigational plan, applicable
FDA regulations, and IRB requirements....
Sandra Maddock

17. Working through the maze
Federal Regulations
Agreements
Investigational Plan
Requirements of IRB
Sandra Maddock

18. Federal Regulations
• Requirements for conducting clinical studies
• Outlines responsibilities of the sponsors,
investigators, and IRBs for conducting trials
involving human subjects

19. Federal Regulations
FDA Regulations to Know
812
IDEs (Investigational Device Exemptions)
50
Protection of Human Subjects
56
IRBs (Institutional Review Boards)
54
Financial Disclosures
11
Electronic Records/Signatures
Sandra Maddock

20. Federal Regulations
21 CFR 812 - IDEs
• Describes the procedures for the conduct
of clinical investigations of devices
• Sponsor responsibilities
• Investigator responsibilities
Sandra Maddock

21. Federal Regulations
21 CFR 812 - IDEs
• 812.110: An investigator shall conduct an investigation in
accordance with the signed agreement with the
Investigator sponsor, the investigational plan, this part and other
applicable FDA regulations, and any conditions of
approval imposed by an IRB or FDA.
• 812.46: (paraphrased) Ensuring compliance with
Sponsor signed agreement, investigational plan, applicable
FDA regulations, and IRB requirements....
Sandra Maddock

22. Federal Regulations
21 CFR 812 - IDEs
• Overall conduct of a study:
– Labeling
– Promotion
– Selection of Investigators
– Monitoring (securing compliance)
– Record keeping
– IRB approval…..
DOCUMENT IT!
Sandra Maddock

23. Federal Regulations
21 CFR 50 – Human Subject Protection
• The rights, safety, and well-being of the trial subjects
should prevail over interests of science and society.
• Freely given Informed Consent should be obtained from
every subject prior to clinical trial participation.
• The confidentiality of records that could identify subjects
should be protected, respecting the privacy and
confidentiality
Sandra Maddock

24. Federal Regulations
21 CFR 50 – Human Subject Protection
• Specifies:
– Consenting procedures
– Elements to include in an informed consent
– Documentation of informed consent
– Exceptions of informed consent
– Safeguards for children/wards
Sandra Maddock

25. Federal Regulations
21 CFR 50 – Human Subject Protection
• Sponsor obligations:
– Ensure informed consent process at site level is
compliant with regulatory requirements
DOCUMENT IT!
Sandra Maddock

26. Federal Regulations
21 CFR 56 - IRBs
• IRBs – Institutional Review Boards (Ethics Committees)
Review and approve research studies involving
human subjects
• 21 CFR part 56 contains general standards for the
composition, operation, and responsibility of an IRB
that reviews clinical investigations regulated by the FDA
Sandra Maddock

27. Federal Regulations
21 CFR 56 - IRBs
An IRB has the authority to:
• Approve research
• Require modifications in research
• Disapprove research
• Require additional elements of informed consent
are provided
• Waive the requirement for a signed informed
consent
Sandra Maddock

28. Federal Regulations
21 CFR 56 - IRBs
• Sponsor’s obligations:
– Ensure IRB is operating in compliance with 21 CFR 56
– Ensure site is following IRB procedures
DOCUMENT IT!
Sandra Maddock

29. Federal Regulations
21 CFR 54 – Financial Disclosure
• Protect the integrity and reliability of clinical data
• FDA considers whether adequate steps are taken in the
design, conduct, reporting and analysis of studies to
minimize bias
• The FDA works with the applicant/sponsor to minimize
potential bias
Sandra Maddock

30. Federal Regulations
21 CFR 54 – Financial Disclosure
Investigator to
Sponsor to FDA
Sponsor
If financial interests raise questions about data integrity
the FDA may:
• Initiate audits of the data from that investigator
• Request further analyses of data
• Request applicant to conduct additional studies
• Refuse the data
Sandra Maddock

31. Federal Regulations
21 CFR 54 – Financial Disclosure
• Sponsor’s obligations:
• Collect accurate investigator financial information before study
participation (21 CFR 812.43)
• Report COI to FDA at time of application
• Obtain updates throughout the study and for one year after all
study data is submitted
DOCUMENT IT!
Sandra Maddock

32. Federal Regulations
21 CFR 11 – Electronic Records
• Describes How:
– Electronic records, electronic signatures,
and handwritten signatures executed to
electronic records are considered
trustworthy, reliable, and generally
equivalent to paper records and
handwritten signatures executed on paper.
Sandra Maddock

33. Federal Regulations
21 CFR 11 – Electronic Records
• To ensure the authenticity, integrity and confidentiality of
electronic records, controls include:
– Tracking of data entry with an audit trail (paper or electronic)
– Documented verification of data entry accuracy
– Unique electronic signatures
Sandra Maddock

34. Federal Regulations
21 CFR 11 – Electronic Records
• Sponsor’s obligation:
– Know the requirements of 21 CFR 11
– Ensure site and internal (sponsor) compliance
DOCUMENT IT!
Sandra Maddock

35. Minute to Win It!
Sandra Maddock

36. Fill in the blanks….
Regarding record maintenance, an investigator must
maintain accurate, complete and current records,
including:
21 CFR 812.140 (1)
All _____________ with another
____________, an _______, the
sponsor, a monitor, or ______,
including required
________________.

37. Working through the maze
Federal Regulations
Agreements
Investigational Plan
Requirements of IRB
Sandra Maddock

38. Agreements
• Statement of investigator’s commitment to:
– Conduct the investigation in compliance with FAIR
– Supervise device use
– Obtain informed consent
– Other items as agreed upon with sponsor…
DOCUMENT IT!
Sandra Maddock

39. Working through the maze
Federal Regulations
Agreements
Investigational Plan
Requirements of IRB
Sandra Maddock

40. Investigational Plan
• Inclusion / Exclusion
• Required Testing
• Procedural Requirements
• Randomization Processes
• Follow-up Requirements
DOCUMENT IT!
Sandra Maddock

41. Working through the maze
Federal Regulations
Agreements
Investigational Plan
Requirements of IRB
Sandra Maddock

42. Requirements of IRB
• Informed consent procedures
• Adverse event reporting requirements
• Renewal timelines
• Etc.
Sandra Maddock

43. Case Maze Study #1
You are monitoring a site when you notice
that an investigator routinely signs the
consent forms days after the patients sign
them. You’re not sure what to do. The
manager of the brand new research
coordinator tells you that this is no big deal
and there is nothing to address.
She said “It’s not in the regs…..” Is she
right?
Sandra Maddock

44. Working through the maze
Federal Regulations
Agreements
Investigational Plan
Requirements of IRB
 Could be specified by the IRB
Sandra Maddock

45. Maze Study #2
A monitor notes that all of the IRB
approvals were on file at a site, but
some of the correspondence back and
forth regarding the approvals was
missing. The RC refused to locate the
missing documentation.
The monitor insists “It’s in the
Regs….” Is the monitor correct?
Sandra Maddock

46. Working through the maze
Federal Regulations
 FDA requires that all correspondence with an IRB be maintained (21 CFR 812.140)
Agreements
Investigational Plan
Requirements of IRB
Sandra Maddock

47. Maze Study #3
You have a site that routinely takes
case report forms (CRFs) into the
exam room while seeing patients.
While much of the information you
need for the study is included in the
patient’s regular assessment, they
write the other data directly onto the
CRF. You think they need a separate
source, but you’re not sure.
You dig into the regulations and find
what???
Sandra Maddock

48. Working through the maze
Federal Regulations
Agreements  Could be in an agreement
 Could be in an
Investigational Plan investigational plan
Requirements of IRB
Sandra Maddock

49. Well?????
Discuss current FDA climate and the impact
that has on the orthopaedic industry
Identify regulations that govern
clinical research and discuss the
importance of having a solid
regulatory basis for decisions made
in the clinical research setting
Apply regulations to
real-world
scenarios
Sandra Maddock

50. Sandra Maddock
CEO and President
Meet Our Team
John Lehman Mary Lewis
Director of Business Development Clinical Auditor & Research Associate
Sandra Maddock

51. More Information for You on
Download our
Whitepaper
Sandra Maddock

53. References
• FDA’s official website:
• www.fda.gov
• GCP Guidances and Information Sheets
• http://www.fda.gov/oc/gcp/guidance.html
• Informed Consent
• A Guide To Informed Consent:
• http://www.fda.gov/oc/ohrt/irbs/informedconsent.html
• Protection of Subjects:
• http://www.fda.gov/cdrh/devadvice/ide/informed_consent.shtml
• Running clinical trials
• http://1.usa.gov/ILt1tc
Sandra Maddock