clinical trial monitoring, auditing and inspection

2nd DIA China Annual Meeting | May 16-19, 2010 | Beijing, China

Clinical Trial Monitoring, Auditing and Inspection

Workshop– FDA,SFDA and Industry Perspective

Ning LI, MD, PhD

Sanofi-Aventis


Disclosure and

Acknowledgements• The following are my views and not

necessarily the views of the US FDA or Sanofi-aventis

• Adapted Some Former FDA colleague’s Presentations at varies Public Events


Foreign Data Acceptance

and GCP Inspections


Globalization of Clinical Trials

• Contribution of non-U.S. data to FDA

applications continues to increase

– About 50% of FDA regulated clinical trials are

conducted outside the U.S. (WSJ 12/1/2008)

– Since 2002, # of foreign CIs has increased 15%/yr, and US CIs has decreased by 5.5% (NEJM, 2/19/09)


FDA’s Rule (21 CFR 312.120)

• FDA’s acceptance as support for an IND or application

for marketing approval (drug or biologic) a well-designed and well-conducted foreign clinical study not conducted

under an IND

– Final rule published April 28, 2008

– Effective 180 days after publication (10/27/08)

• Applicable to foreign clinical studies on the effective date

regardless of the status of subject enrollment (e.g., ongoing,

completed, not yet initiated)


Acceptance of foreign data in support of research or marketing

in U.S.

– Foreign studies conducted under IND

– Not conducted under an IND, but meeting criteria

specified in FDA regulations


Requirements [312.120]

• Sponsor who wishes to rely on a foreign clinical study to

support IND or application for marketing approval shall submit to FDA a description of actions taken to ensure

research conformed to GCP

– Description of investigator’s qualifications

– Description of research facilities

– Detailed summary of protocol and results of study, and should FDA request, case records maintained by the investigator or additional background data such as hospital records


Requirements (con’t)

• Description drug product, including components,

formulation, specifications and bioavailability, if available

• If study intended to support effectiveness, information

showing study is adequate and well controlled

• Name and address of IEC that reviewed the study and a

statement that the IEC meets the definition in 312.3

• Summary of IEC’s decision to approve or modify and

approve, or to provide a favorable opinion


Requirements (con’t)

• Description of how IC obtained

• Description of incentives, if any, to subjects

• Description of how sponsors monitored and ensured study was consistent with protocol

• Description of how investigators trained to comply with GCP and conduct study in accordance with protocol, and a statement on whether written commitments by investigators to comply with GCP and protocol were obtained


Record Requirements [312.120]

A sponsor or applicant must retain records required by this

section for a foreign clinical study not conducted under IND as follows:

– If study submitted in support of marketing application, for 2 years after an agency decision on that application;

– If the study is submitted in support of an IND but not a marketing application, for 2 years after submission of the IND


Foreign data as sole basis to support FDA marketing approval [314.106]

– Data are applicable to US population and medical practice

– Studies are performed by investigators of recognized competence

– Data are considered valid without an on-site FDA inspection

– FDA is able to validate the data through an on-site inspection


Case/Example

– CCS 2 Study ~45000 Chinese patients

– Plavix for secondary prevention

– Endpoint: MACE

– 400+ sites in China

– FDA conducted on-site inspection in 5 China site and found no major deficiencies

– NDA was approved.


Summary of acceptability

• Conducted under U.S. IND– Must meet same requirements of U.S. regs

• FDA may accept foreign studies NOT conducted under IND if the studies are:

– Well designed– Well conducted– Performed by qualified investigators– Conducted in accordance with GCP– FDA is able to validate data through onsite inspection if

necessary


• Foreign Inspectional Activity


Clinical Trials in the U.S.

• Estimated 7600 clinical studies (2002 )

• Average of 12 sites/study

• Therefore, approximately 91,200 sites

• Growing at approximately 10% per year


Evaluation of Findings

• Major deviations from the regulations, requiring official action, are relatively rare in domestic clinical investigator inspections.

• But serious data quality and integrity problems are observed more frequently in foreign vs. domestic pivotal studies.


GCP Deficiencies non-U.S. vs US

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

US

Non-US

RecordsProtocol Drug

Accountability

Consent FormAdverse

Events

50% 48%

25%20%

14%

25%21%20%

13%

5%


Clinical Investigator Deficiencies

0%

5%

10%

15%

20%

25%

30%

35%

40%

Protocol Records Consent Drug Acct AEs

Foreign

Domestic

31%

34% 36%

27%

22%

9%

22%

12%

25%

7%

Foreign n = 36Domestic n = 233


Criteria for International

Inspections

International sites may be audited

– if there are insufficient domestic data;

– only foreign data are submitted to support an application;

– domestic and foreign data show conflicting results pertinent

to decision-making; or

– there is a serious issue to resolve, e.g., suspicion of fraud,

scientific misconduct, significant human subject protection

violations.


Clinical Inspections - International

(CDER, FY 1992 - 2004)

0

10

20

30

40

50

60

70

80

90

91-95*

96

97

98

99

2000

2001

2002

2003

2004


Clinical Investigator Inspections-International*


Clinical Investigator Inspection*CDER FY 2001-2009**


Sites of International Inspections

1980 - 2003*Germany 36

Greece 2

Guatemala 2

Hong Kong 3

Hungary 6

Ireland 1

Israel 4

Italy 27

Japan 3

Kenya 1

Latvia 3

Lithuania 1

Malawi 1

Mexico 8

Netherlands 19

New Zealand 3

Nigeria** 1

Norway 3 Panama 1Peru 4Philippines 1Poland 8Portugal 2Romania 1Russia 11Slovenia 1South Africa 16Spain 14Sweden 24Switzerland 1Taiwan 1Thailand 1U. K. 75Venezuela 2Zambia 1

Algeria** 1Argentina 6Australia 5Austria 5Bahamas 1Belgium 16Brazil 6Canada 106Chile 1China 2Costa Rica 5Czechoslovakia 3Croatia 2Denmark 8Dominican Rep. 1Egypt 1Finland 13France 39Gabon 1

*through 9/30/03

**data reviewed in U.S.


Sites of International Inspections 1980 - 2009*

Gabon 1

Germany 63

Greece 3

Guatemala 2

Hong Kong 6

Hungary 13

Ireland 1

Israel 5

Italy 40

Japan 9

Kenya 2

Latvia 9

Lithuania 2

Malawi 1

Malaysia 1

Mexico 15

Netherlands 26

New Zealand 4

Nigeria** 1

Norway 6 Panama 2Peru 7Philippines 2Poland 33Portugal 3Republic of Korea 6Romania 10Russia 63Slovenia 2South Africa 32Spain 16Sweden 31Switzerland 3Taiwan 1Thailand 7U. K. 104Ukraine 3Venezuela 2Zambia 1

Algeria** 1Argentina 23Australia 13Austria 7Bahamas 1Belgium 29Brazil 13Canada 192Chile 5China 14Columbia 1Costa Rica 8Croatia 12Czechoslovakia 18 Denmark 18Dominican Rep. 1Estonia 5Egypt 1Finland 15France 60


CDER – DSI International Clinical Investigator BIMO Inspections*: FY 2009**


Site Selection and Site

Selection Tool


Clinical Trial Pre-Approval

Inspection Process

• Joint effort across multiple functions

– Office of New Drugs (OND) reviewers select applications

– OND reviewers work jointly with Division of Scientific Investigations (DSI) reviewers and Office of Biostatistics reviewers to choose sites

– FDA’s Office of Regulatory Affairs (ORA) inspectors work jointly or independently to inspect clinical sites, sponsors, CROs


Effect of Inspections on Approval

• If data quality or integrity problems are detected, the

following actions may occur.

--depending on the scope, nature and risk

• No effect on approval; approval may be granted

• Approval may be delayed for further inspections and

analysis

• Post-marketing studies may be required

• Non-approval


Drug Information Association www.diahome.org

Site Selection:

Site selection should focus on:

– Impact to review of the study

• Largest site

• Outliers, e.g., site with large proportion of responders/trt effect

• Drop-outs; adverse events; protocol violations

• Smaller than average variation in patient response

– Impact to the clinical trial process

• Volume of FDA-regulated research performed by the Clinical Investigator

• Past inspectional history

• Open door policy to reports of scientific misconduct


Site Selection: Additional Considerations

• Suspicion of false or fraudulent data

• Data that appear unrealistic

• Evidence that a sponsor has rejected data from an investigator

• Evidence of under-reporting or delay in submitting adverse events

• Evidence of inadequately monitored clinical investigations

• Evidence of inadequate or inappropriate informed consent

• Evidence of delayed or inappropriate IRB approval

• Evidence that an investigator has a significant financial interest in the product


• The number of subjects enrolled/randomized/completing the study per site

• Sites demonstrating the greatest point estimates of efficacy (primary endpoint)

• Site-specific differences in between-subject variability in treatment response

• Number and type of reported adverse experiences by site• Number of protocol violations by site• Number of premature withdrawals by site• Multiple pivotal trials conducted by the same investigator

(supporting same application)

Site Selection: Additional Considerations (cont.)


Challenges to the current inspection system

• This approach does not allow generalization

of inspectional findings

– Don’t know how representative inspected

investigators are of all clinical investigators

• For most applications, a statistical approach

(random sampling with statistical significance)

would require inspection of more sites per

application.


Challenges to the current inspection

system

• Finite inspectional resources limit the number of inspections

• Increasing number of sites per clinical trial

• Increasing number of foreign clinical trial sites

• PDUFA timelines require high level of efficiency

• Variation exists in CDER’s site selection methodology

• Lack of data standards in sponsor submissions can delay analysis time


Site Selection Tool:

• Project Scope:

– To support prioritization of clinical trial sites for inspection as part of pre-approval review

– Define a multi-attribute algorithm to score clinical site/investigator risk

• Goals:

– Develop a more consistent, science-based approach to clinical site inspection

– Enable deployment of limited resources towards sites that pose the potentially greatest risk to public health

– Significantly reduce time and effort required to select sites


Model Attributes

Three levels of risk attributes:

• Application level

–Submission type, Population Vulnerability, Severity of disease, Target

population size, Impact of Indication

• Study level

–Pivotal Status, Trial Design Type, Geography of Trial

• Clinical Site level

–Enrollment, Site Specific Efficacy, Protocol Deviations, AEs, SAEs, Percentage of Subject

Deaths, Enroll/Screen Percentage, Subject Discontinuations, Financial Disclosure (FD),

–Clinical Investigator Complaints, Inspection History


Advantages and Considerations

• Risk ranking of sites provides a framework for site selection

• Assembles site characteristics in one tool

• Provides standard data exploration methodology

• Improves data analysis time

• Automated documentation and form generation

• Tool is an aid for reviewers to select sites

• Does not replace the reviewer

• The tool gives the user the ability to choose sites based on risk scores and

other considerations.

clinical trial monitoring, auditing and inspection

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