sandra maddock omtec presentation 6-12
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TRANSCRIPT
We have studied clinical research and regulatory compliance
issues since 1999.
Running a Clinical Trial:
How to Navigate the
Regulatory Maze
Presented by:
Sandra Maddock, RN, BSN, CCRA
President & CEO, IMARC Research, Inc.
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
Our Focus: Clinical
Development Design/Prototype
Validation/Verification
Preclinical Testing
Clinical
Regulatory Clearance
Post Market Activities
Sandra Maddock
Our Focus: Clinical
Clinical
Sandra Maddock
Research involving human
subjects….
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
Current FDA Climate
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January, 2012 – “Device industry watchers say FDA’s new overarching draft guidance on the 510(k) pre-market review program introduces new concepts that may add confusion, not clarity, to device makers planning to bring new products to market.”
Current FDA Climate
Sandra Maddock
“(FDA changes) could result in significant disruption to a program that has served patients well for more than 30 years.” Quote from AdvaMed
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
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
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Let’s Shake Things Up
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“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
You Need To Bring It!
Sandra Maddock
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
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;
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;
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 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
CFR 56; ICH; IRB SOPs; SPONSOR SOPs; SITE SOPs; AGREEMENTS; PROTOCOL; 21 CFR 812; 21 CFR 11;
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;
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; ICH; IRB SOPs; SPONSOR SOPs; SITE 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!
Sponsor
Sponsor Requirements
Good Clinical Practice
FDA Regulations
ICH Guidelines
Protocol Requirements Investigator
Agreements
ISO14155
NIH Guidelines
IRB Requirements
Internal Policies
What You Need to Know
CRO/
Monitor
Research
Site
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Adding To The Mix…
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….
Variable
Fixed versus
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Sandra Maddock
21 CFR 812 - IDEs
• 812.110: An investigator shall conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.
Investigator
• 812.46: (paraphrased) Ensuring compliance with signed agreement, investigational plan, applicable FDA regulations, and IRB requirements....
Sponsor
Sandra Maddock
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
• Requirements for conducting clinical studies
• Outlines responsibilities of the sponsors,
investigators, and IRBs for conducting trials
involving human subjects
Federal Regulations
IDEs (Investigational Device Exemptions)
Protection of Human Subjects
IRBs (Institutional Review Boards)
Financial Disclosures
Electronic Records/Signatures
11
50
56
54
812
FDA Regulations to Know
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Federal Regulations
• Describes the procedures for the conduct
of clinical investigations of devices
• Sponsor responsibilities
• Investigator responsibilities
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Federal Regulations
21 CFR 812 - IDEs
• 812.110: An investigator shall conduct an investigation in accordance with the signed agreement with the sponsor, the investigational plan, this part and other applicable FDA regulations, and any conditions of approval imposed by an IRB or FDA.
Investigator
• 812.46: (paraphrased) Ensuring compliance with signed agreement, investigational plan, applicable FDA regulations, and IRB requirements....
Sponsor
Sandra Maddock
Federal Regulations
21 CFR 812 - IDEs
Sandra Maddock
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!
• 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
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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
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
Federal Regulations
21 CFR 50 – Human Subject Protection
• 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
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
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
Federal Regulations
21 CFR 56 - IRBs
• 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
Federal Regulations
21 CFR 54 – Financial Disclosure
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
Investigator to Sponsor
Sponsor to FDA
Sandra Maddock
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
Federal Regulations
21 CFR 54 – Financial Disclosure
• 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
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
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
Federal Regulations
21 CFR 11 – Electronic Records
Minute to Win It!
Sandra Maddock
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
________________.
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
• 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…
Sandra Maddock
Agreements
DOCUMENT IT!
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
• Inclusion / Exclusion
• Required Testing
• Procedural Requirements
• Randomization Processes
• Follow-up Requirements
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Investigational Plan
DOCUMENT IT!
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
Sandra Maddock
Requirements of IRB
• Informed consent procedures
• Adverse event reporting requirements
• Renewal timelines
• Etc.
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?
Case Maze Study #1
Sandra Maddock
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB Could be specified by the IRB
Maze Study #2
Sandra Maddock
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?
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
FDA requires that all correspondence with an IRB be maintained (21 CFR 812.140)
Maze Study #3
Sandra Maddock
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???
Working through the maze
Sandra Maddock
Federal Regulations Agreements Investigational Plan
Requirements of IRB
Could be in an agreement
Could be in an
investigational plan
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
Mary Lewis Clinical Auditor & Research Associate
Sandra Maddock CEO and President
John Lehman Director of Business Development
Meet Our Team
Sandra Maddock
More Information for You on
Download our
Whitepaper
Sandra Maddock
• 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
References
Sandra Maddock