ensuring quality in medical device clinical trials paul below, ccra clinical research consultant p....

Ensuring Quality in Medical Ensuring Quality in Medical Device Clinical TrialsDevice Clinical Trials

Paul Below, CCRAPaul Below, CCRAClinical Research ConsultantClinical Research ConsultantP. Below ConsultingP. Below Consulting

Great Plains Chapter ACRPGreat Plains Chapter ACRPOmaha, NEOmaha, NEOctober 25, 2007October 25, 2007

This presentation is based This presentation is based upon similar recent upon similar recent presentations and articles by presentations and articles by Michael Marcarelli, Director, Michael Marcarelli, Director, Division of Bioresearch Division of Bioresearch Monitoring, Office of Monitoring, Office of Compliance, Center for Compliance, Center for Devices and Radiological Devices and Radiological Health (CDRH)Health (CDRH)

Picture Source: Medical Device & Diagnostic Industry (Jul 2006): pg. 60.

AcknowledgementAcknowledgement

I do not have a financial interest, arrangement I do not have a financial interest, arrangement or affiliation with a commercial organization or affiliation with a commercial organization that may have a material interest in the subject that may have a material interest in the subject matter of my presentation.matter of my presentation.

DisclosureDisclosure

Describe the FDA’s Bioresearch Monitoring Describe the FDA’s Bioresearch Monitoring Program (BIMO).Program (BIMO).

Review CDRH BIMO inspection activities Review CDRH BIMO inspection activities and results.and results.

Describe common sponsor and investigator Describe common sponsor and investigator deficiencies found during inspections.deficiencies found during inspections.

Discuss strategies that sponsors can Discuss strategies that sponsors can employ to improve GCP compliance and employ to improve GCP compliance and clinical trial quality.clinical trial quality.

Learning ObjectivesLearning Objectives

Established in 1977 and expanded in 1992.Established in 1977 and expanded in 1992.

Comprehensive program of on-site inspections and Comprehensive program of on-site inspections and data audits to monitor all aspects of the conduct and data audits to monitor all aspects of the conduct and reporting of FDA regulated research. reporting of FDA regulated research.

Each FDA Center has its own BIMO program staff with Each FDA Center has its own BIMO program staff with overall coordination by the Office of Regulatory Affairs. overall coordination by the Office of Regulatory Affairs.

Implemented domestically and internationally resulting Implemented domestically and internationally resulting in over 1000 inspections annually.in over 1000 inspections annually.

BIMO Program OverviewBIMO Program Overview

To ensure the quality and integrity of data To ensure the quality and integrity of data submitted in support of investigational and submitted in support of investigational and marketing clearance submissions [IDEs, marketing clearance submissions [IDEs, PMAs, and 510(k)s].PMAs, and 510(k)s].

To ensure that human subjects taking part in To ensure that human subjects taking part in investigations are protected from undue investigations are protected from undue hazard or risk.hazard or risk.

BIMO Program ObjectivesBIMO Program Objectives

Clinical InvestigatorsClinical Investigators

Sponsors/Monitors/CROsSponsors/Monitors/CROs

Institutional Review BoardsInstitutional Review Boards

Non-Clinical Labs (aka GLP)Non-Clinical Labs (aka GLP)

Who is Inspected?Who is Inspected?

CDRH BIMO Inspection RatesCDRH BIMO Inspection Rates

357 353 350332 336

100

200

300

400

500

FY02 FY03 FY04 FY05 FY06

Source: “Device Clinical Trials and More….”, Michael E. Marcarellii, MassMEDIC, May 2007

CDRH Inspection CategoriesCDRH Inspection Categories

Inspected Entity

2002 2003 2004 2005 2006

Sponsor 7272 8181 7373 7070 5353

Investigator 151151 170170 183183 183183 200200

IRB 128128 8585 7373 4848 5959

Lab 66 99 1919 3131 2424


Inspections by FDA Center (05)Inspections by FDA Center (05)

Inspected Entity CDER CBER CDRH

Sponsor 3131 55 7070

Investigator 382382 9898 183183

IRB 113113 1010 4848

TOTAL 526526 113113 301301

Source: FDA Website

Marketing application submissionMarketing application submission

Novel technologyNovel technology

Vulnerable populationVulnerable population

ComplaintComplaint

CDRH Inspection TriggersCDRH Inspection Triggers

FDA field inspectors from 19 district offices conduct FDA field inspectors from 19 district offices conduct inspections (according to BIMO Compliance Program inspections (according to BIMO Compliance Program Manuals 7348.808-811).Manuals 7348.808-811).

After inspection, FDA field inspector writes an establishment After inspection, FDA field inspector writes an establishment inspection report (EIR).inspection report (EIR).

After district office review, the completed EIR package is sent After district office review, the completed EIR package is sent to CDRH BIMO.to CDRH BIMO.

Once the EIR is received, it is assessed and classified by Once the EIR is received, it is assessed and classified by CDRH.CDRH.

Inspection ProcessInspection Process

BIMO Review MilestonesBIMO Review Milestones

Source: “Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., MDDI (Oct 2006)

No Action Indicated (NAI)No Action Indicated (NAI) = the FDA field = the FDA field inspector did not identify objectionable inspector did not identify objectionable practices or identified only minor issues that practices or identified only minor issues that did not justify further action.did not justify further action.

Voluntary Action Indicated (VAI)Voluntary Action Indicated (VAI) = indicates = indicates that objectionable practices were uncovered that objectionable practices were uncovered during the inspection, but were not significant.during the inspection, but were not significant.

Inspection ClassificationsInspection Classifications

Official Action Indicated (OAI)Official Action Indicated (OAI) = inspection = inspection uncovered significant objectionable practices, which uncovered significant objectionable practices, which could affect data reliability or compromise human could affect data reliability or compromise human subject protection. Generally results in the issuance subject protection. Generally results in the issuance of a Warning Letter or some other higher-level of a Warning Letter or some other higher-level compliance action.compliance action.

15 day response required - failure to take action may 15 day response required - failure to take action may result in administrative or regulatory action without result in administrative or regulatory action without further notice.further notice.

Inspection ClassificationsInspection Classifications

CDRH Warning LettersCDRH Warning Letters

7

20 18

10

6

3

7

3

3

1

17

24

7

7

2

3

0

10

20

30

40

50

FY02 FY03 FY04 FY05 FY06

GLP

IRB

Sponsor

CI


Investigator ComplianceInvestigator Compliance


11%15% 17%

21%

11%

17%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAI

VAI

OAI

Sponsor ComplianceSponsor Compliance


19%

10%

24%

31%

15%11%

0%

10%

20%

30%

40%

50%

60%

70%

10 Years FY02 FY03 FY04 FY05 FY06

NAIVAIOAI

Long-term OAI rates:Long-term OAI rates: CDRH = 13%CDRH = 13%

CDER = 3%CDER = 3%

Investigator warning letters issued in 2005:Investigator warning letters issued in 2005: CDRH = 20CDRH = 20

CDER = 2CDER = 2

CBER = 4CBER = 4

OAI Rates by FDA Center OAI Rates by FDA Center

Source: “Improving Clinical Compliance in the Medical Device Industry,” Barry Sall, MDDI, March 2006 & FDA Website

Investigator DeficienciesInvestigator Deficiencies


Sponsor DeficienciesSponsor Deficiencies


Marcarelli has proposed the following methods Marcarelli has proposed the following methods for sponsors to improve GCP compliance and for sponsors to improve GCP compliance and clinical trial quality:clinical trial quality:

Implement a Quality Systems approach to the Implement a Quality Systems approach to the oversight and management of clinical trialsoversight and management of clinical trials

Employ the five habits of “highly effective” sponsorsEmploy the five habits of “highly effective” sponsors

Improving QualityImproving Quality

Quality systems regulations for medical devices are Quality systems regulations for medical devices are part of GMP and highlighted in part of GMP and highlighted in 21 CFR part 820.21 CFR part 820.

Covers quality management and organization, device Covers quality management and organization, device design, buildings, equipment, purchase and handling design, buildings, equipment, purchase and handling of components, production and process controls, of components, production and process controls, packaging and labeling control, device evaluation, packaging and labeling control, device evaluation, distribution, installation, complaint handling, servicing, distribution, installation, complaint handling, servicing, and records. and records.

Quality Systems Quality Systems

The most useful element of the quality system, as it The most useful element of the quality system, as it applies to clinical studies, is the application of a applies to clinical studies, is the application of a Corrective and Preventive Action (CAPA) program.Corrective and Preventive Action (CAPA) program.

CAPA entails the following:CAPA entails the following: Problems are identified and investigatedProblems are identified and investigated Root causes are identifiedRoot causes are identified Corrective and preventive actions are identified and Corrective and preventive actions are identified and

implementedimplemented Actions are tracked and effectiveness is verifiedActions are tracked and effectiveness is verified

Quality Systems - CAPAQuality Systems - CAPA

Submit information for management review Submit information for management review on identified problems and actions taken.on identified problems and actions taken.

Track the progress and resolution of each Track the progress and resolution of each case.case.

Quality Systems - CAPAQuality Systems - CAPA

Scenario:Scenario: During routine monitoring, a CRA During routine monitoring, a CRA identifies several trial subjects who did not identifies several trial subjects who did not meet study inclusion/exclusion criteria. The meet study inclusion/exclusion criteria. The site was not aware of these violations and site was not aware of these violations and had not reported them to the sponsor or IRB.had not reported them to the sponsor or IRB.

What is the What is the root causeroot cause of these deficiencies? of these deficiencies?

CAPA ExampleCAPA Example

Forgot protocol requirements?

Lack of PI oversight?

Overwork/too busy?

Apathy?

Inadvertent error?

What needs to be done to immediately What needs to be done to immediately correct correct these deficiencies?these deficiencies?

Promptly report to sponsor and IRBPromptly report to sponsor and IRB

Determine if subject can continue participation in Determine if subject can continue participation in the studythe study

Ensure adequate documentation of deviation is Ensure adequate documentation of deviation is added to the source documentsadded to the source documents

Suspend further enrollment?Suspend further enrollment?


What can be done to What can be done to preventprevent these deficiencies from these deficiencies from occurring again?occurring again?

Additional training on protocolAdditional training on protocol

Provide protocol reference materials such as pocket Provide protocol reference materials such as pocket cardscards

Ensure investigator review of criteria prior to study Ensure investigator review of criteria prior to study

Require additional or new study staffRequire additional or new study staff

Require sponsor review of screening data and OK prior to Require sponsor review of screening data and OK prior to randomizationrandomization


How will these deficiencies be submitted for How will these deficiencies be submitted for management management reviewreview??

Documented in monitoring reportDocumented in monitoring report Cataloged in databaseCataloged in database Discussed during regular project team meetingsDiscussed during regular project team meetings

How will this CAPA issue be How will this CAPA issue be trackedtracked until resolution? until resolution? Follow-up by CRA documented in “pending action items” Follow-up by CRA documented in “pending action items”

section of monitoring reportsection of monitoring report Issue “closed out” in database when resolvedIssue “closed out” in database when resolved


BIMO reviewed all device sponsor audits BIMO reviewed all device sponsor audits classified as NAI by the division between October classified as NAI by the division between October 2003 and February 2006.2003 and February 2006.

The division diligently reviewed and evaluated all The division diligently reviewed and evaluated all the information noted by FDA field inspectors in the information noted by FDA field inspectors in the EIRs and found common threads, which the EIRs and found common threads, which translated into what they termed as the “Five translated into what they termed as the “Five Habits of Highly Effective Device Sponsors.” Habits of Highly Effective Device Sponsors.”

5 Habits of Effective Sponsors5 Habits of Effective Sponsors

#1 – Establish SOPs#1 – Establish SOPs for such functions as investigator for such functions as investigator site selection, adverse event reporting, data handling, site selection, adverse event reporting, data handling, clinical site initiation, personnel training and site clinical site initiation, personnel training and site monitoring.monitoring.

#2 – Hire employees with experience#2 – Hire employees with experience in conducting in conducting studies, e.g., managers with a background in clinical studies, e.g., managers with a background in clinical studies; subject matter experts for protocol development; studies; subject matter experts for protocol development; monitors with clinical backgrounds; and regulatory monitors with clinical backgrounds; and regulatory personnel with expertise in clinical trial regulations.personnel with expertise in clinical trial regulations.


#3 – Utilize consultants#3 – Utilize consultants such as Contract Resource such as Contract Resource Organizations (CROs) for study functions beyond the Organizations (CROs) for study functions beyond the sponsor’s in-house capabilities.sponsor’s in-house capabilities.

#4 – Conduct internal/external audits#4 – Conduct internal/external audits of clinical of clinical study processes, procedures and personnel to study processes, procedures and personnel to include regular audits of the clinical study department include regular audits of the clinical study department and its related procedures, and regular on-site audits and its related procedures, and regular on-site audits of monitoring personnel and the monitoring process.of monitoring personnel and the monitoring process.


#5 – Management review of clinical study #5 – Management review of clinical study issuesissues by personnel with executive by personnel with executive responsibilities. This review includes analyzing responsibilities. This review includes analyzing clinical study progress reports during clinical study progress reports during management review meetings and presenting management review meetings and presenting problem reports to top executives in real time.problem reports to top executives in real time.


““Device Clinical Trials and More…”, Michael Marcarelli (presented to Device Clinical Trials and More…”, Michael Marcarelli (presented to MassMEDIC on May 18, 2007) (MassMEDIC on May 18, 2007) (www.massmedic.com/docs/cdrh07.pptwww.massmedic.com/docs/cdrh07.ppt))

““Building Quality into Device Clinical Trials, Part 1,” Michael E. Building Quality into Device Clinical Trials, Part 1,” Michael E. Marcarelli et al., Marcarelli et al., MDDIMDDI (Jul 2006): pg. 60 ( (Jul 2006): pg. 60 (www.devicelink.com/mddi/archive/06/07/011.htmlwww.devicelink.com/mddi/archive/06/07/011.html))

““Building Quality into Device Clinical Trials, Part 2,” Michael E. Building Quality into Device Clinical Trials, Part 2,” Michael E. Marcarelli et al., Marcarelli et al., MDDIMDDI (Oct 2006): pg. 56 ( (Oct 2006): pg. 56 (www.devicelink.com/mddi/archive/06/10/015.htmlwww.devicelink.com/mddi/archive/06/10/015.html))

““Five Habits of Highly Effective Device Sponsors,” Michael Marcarelli, Five Habits of Highly Effective Device Sponsors,” Michael Marcarelli, The MonitorThe Monitor (Feb 2007): pg. 83 (Feb 2007): pg. 83

ReferencesReferences

““Improving Clinical Compliance in the Medical Device Industry,” Improving Clinical Compliance in the Medical Device Industry,” Barry Sall, Barry Sall, MDDIMDDI, March 2006 (, March 2006 (www.devicelink.com/mddi/archive/06/03/016.htmlwww.devicelink.com/mddi/archive/06/03/016.html))

““An Interview with Michael Marcarelli: Improvements Seen in the An Interview with Michael Marcarelli: Improvements Seen in the Oversight of Medical Device Research,” Susan Rockwell, Oversight of Medical Device Research,” Susan Rockwell, The The MonitorMonitor (Apr 2006): pg. 62 (Apr 2006): pg. 62

CDRH BIMO Program Website (online at CDRH BIMO Program Website (online at http://http://www.fda.gov/cdrh/comp/bimo.htmlwww.fda.gov/cdrh/comp/bimo.html))

FDA BIMO Compliance Program Manuals (online at FDA BIMO Compliance Program Manuals (online at www.fda.gov/ora/cpgm/default.htm#bimowww.fda.gov/ora/cpgm/default.htm#bimo))

ReferencesReferences

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www.pbelow-consulting.com/devices.htmlwww.pbelow-consulting.com/devices.html

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ensuring quality in medical device clinical trials paul below, ccra clinical research consultant p....

Documents

bimo program overview

bimo program staff

bimo program objectives

clinical trial quality

disclosure slide

acknowledgement slide

glp nonclinical labs

fda center