Sandra Maddock OMTEC Presentation 6-12

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

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Our Focus: Clinical

Clinical

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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

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January, 2012 – “Device industry watchers say FDA’s new overarching draft guidance on the 510(k) pre-market review program introduces new concepts that may add confusion, not clarity, to device makers planning to bring new products to market.”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

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“(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

Sandra Maddock

“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

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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

•

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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

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Working through the maze

Sandra Maddock

Federal Regulations Agreements Investigational Plan

Requirements of IRB Could be specified by the IRB

Maze Study #2

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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

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More Information for You on

Download our

Whitepaper

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• 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