Clinical Trials ConferenceJuly 17, 2007

Bradley Merrill ThompsonEpstein Becker & Green, PC

Managing and Complying with Clinical Quality

Obligations

Topics1. Importance of quality assurance

2. Overview of risk management approach

3. Good Clinical Practices

4. GCP experience

5. Quality and risk management techniques

Importance of Quality Assurance

• More studies; more sites; greater volume

• Expansion and fluidity of clinical investigator pool

• New players in new roles (CROs, SMOs)

• New technologies (electronic recordkeeping)

• More participation by vulnerable subjects

• Global expansion (areas new to GCP)

Quality Requirements (ISO 9000)

• A quality requirement is a characteristic that a product or service must have to satisfy needs and expectations of the customer

requirements

The end product of clinical research

• A product is an output from a process

• The output from the clinical research process is information

trial protocol

collectionof data

poolingof datain the

database

analysis trialreport

Quality in clinical research may be defined as . . .

• Reliability and credibility of information providing an answer to a scientific question

• Compliance of the trial process with defined requirements

A question

An answer

Collection & analysis of data

Customers of clinical research

• Society / consumers

• Research subjects

• Sponsors

• Regulatory authorities worldwide

• Hospitals / institutions

• Ethics committees

Clinical research customers’ requirements

Law & Regulations:EU Directives

US CFRlocal legislation

Ethical Standards:Declaration of Helsinki Good Practice Standards:

GXPs:ICH GCP, ICH GMP, OECD GLP

Topics

1. A quality assurance approach

2. Overview of risk management approach

3. Good Clinical Practices

4. GCP experience

5. Quality and risk management techniques

Risk Management

• Product Risk– FDA does, and you should, consider the intrinsic risk

of the product you are investigating, when deciding the level of sophistication and elegance of your quality system.

– Product risk is a function of:• Technology• Disease or condition• Setting• User

– Remember that the clinical trials quality system is a design input under device QSR, in addition to being subject to Good Clinical practices

– Systems require very similar approach and philosophy

Risk Management

• Commercial Risk– FDA does, and you should, consider the

commercial complexity of the structure of the clinical trial you are organizing when deciding the level of sophistication and elegance of your quality system and the extent of training needed

• Use of CROs, sub-investigators, and so forth

– The more complexity, the greater the burden to manage it well

Risk Management

• Drive it with data– Study your products– Study the commercial arrangements

to identify risks and weaknesses– Study FDA experience inspecting

clinical trials– Study litigation brought against

sponsors– Study reports investigating clinical trial

quality

Why? If you don’t, you might …

• Harm patients• Liability to patients• Data from expensive studies

disqualified from use in FDA submissions– Or expensive fixes required

• Civil and criminal liability to federal and state regulators– Such as OIG, FDA, and state

agencies

FDA Regulatory Actions

• Rejection of data• Deficiency letter• IDE, 510(k), or

PMA withdrawal• Untitled letters• Warning letters• Consent Agreement• Disqualification

– CI, IRB, GLP

• IRB restrictions– No new studies or

subjects• Application Integrity

Policy• Civil Money

Penalties• Seizure / Detention• Injunction• Criminal Prosecution

Topics1. Importance of quality assurance2. Overview of risk management

approach 3. Good Clinical Practices

A. What are they?B. Where do you find them?

4. GCP experience5. Quality and risk management

techniques

What are Good Clinical Practices?

• GCPs are the rules—and self-determined standards—governing clinical research

• GCPs promote scientific and ethical quality in the conduct of clinical trials

• For clinical trials, GCPs set standards for the:Design

Conduct Performance

MonitoringAuditing

Recording Analysis

Reporting

What are they?

1. Ethics: Clinical trials should be conducted in

accordance with the ethical principles that

have their origin in the Declaration of Helsinki,

and that are consistent with GCP and the

applicable regulatory requirement(s).

2. Risk/Benefit: Before a trial is initiated,

foreseeable risks and inconveniences should

be weighed against the anticipated benefit for

the individual trial subject and society. A trial

should be initiated and continued only if the

anticipated benefits justify the risks.

What are they?

3. Protection: The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.

4. Well-Supported: The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial.

5. Scientifically sound: Clinical trials should be scientifically sound, and described in a clear, detailed protocol.

What are they?

6. IRB Review: A trial should be conducted in compliance with the protocol that has received prior intuitional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion.

7. Doctor Managed: The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician, or, when appropriate, of a qualified dentist.

What are they?

8. Well-staffed: Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s).

9. Informed Consent: Freely given informed consent should be obtained from every subject prior to clinical trial participation.

10. Record keeping: All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification.

What are they?

11. Confidentiality: The confidentiality of records that could identify subjects should be protected, respecting the privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).

12. Products: Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). They should be used in accordance with the approved protocol.

What are they?

13. SOP Driven: Systems with procedures that assure the quality of every aspect of the trial should be implemented.

14. Others: Country specific requirements also must be factored in, such as financial conflict of interest and investigator payment rules

Basic US sponsor obligations

• Select qualified investigators• Provide sufficient information to

investigators to conduct the trial• Oversee the trial and enforce compliance• Monitor trial progress• Conduct safety analyses, provide

notification, and submit reports (when appropriate)

• Keep appropriate records• Review and evaluate safety and

effectiveness

Basic US investigator obligations

• Ensure IRB review• Protect the rights and welfare of trial

subjects• Obtain informed consent• Follow the protocol• Personally supervise the study and clinical

staff• Report adverse events• Submit appropriate financial disclosures• Keep appropriate records

Where do you find them in US?

A Tale of Two Systems • In the US, the standards actually vary

depending on the purpose of the clinical trial. – FDA rules for trials that will be conducted

on articles subject to regulation by FDA and for possible submission to FDA

– HHS (common rule) for research conducted or supported by HHS and those who voluntarily agree to be bound (federal-wide assurance)

– Both sets of standards can apply

Clinical research customers’ requirements

Common Rule• HHS IRB• HHS informed

consent• HHS reporting

obligations• HHS guidance

US FDA• FDA IRB• FDA informed consent• FDA Part 812 investigator

and sponsor obligations• FDA Part 312 investigator

and sponsor obligations• Investigator financial conflict• Drug and device quality

system requirements• FDA Part 11 electronic

records• FDA guidance

Both• Fraud and abuse,

antikickback, false claims

• HIPAA• Industry standards

(e.g., PhRMA Principles)

• State law privacy• Other state law

International Conference on Harmonization (ICH) Tripartite Guideline for GCP (1996)

• Provides a unified standard for the conduct of clinical trials in Japan, US, and EU

• Facilitates the mutual acceptance of clinical data by regulatory authorities in Japan, US, and EU

• Assures the safety and protection of clinical trial subjects

• Ensures the credibility of data collected in clinical trials

1. Importance of quality assurance

2. Overview of risk management approach

3. Good Clinical Practices

4. GCP experienceA. FDA’s experience enforcing them

B. Sponsor’s experience defending them

C. Studies examining weaknesses

5. Quality and risk management techniques

Topics

Clinical investigator inspections

What does FDA look for during the inspection?

The FDA Inspection (Audit) compares

• Source Medical Record Datavs

• Case Report Formsvs

• Data Listing Submitted to NDA

Clinical investigator inspections

• Clinical Investigator inspection determines

– Source of subjects

– Did subjects exist?

– Did they have the disease/condition under study?

– Did they meet inclusion/exclusion criteria?

– Consent obtained?

– IRB review and approval obtained?

Clinical investigator inspections

• Clinical Investigator inspection determines– Did the subjects receive the assigned

study drug in the dose, route and frequency specified by the protocol?

– Are the case report forms complete and in agreement with source data? Compare with NDA data listing.

– Are adverse experiences reported to sponsor and IRB?

– Was the protocol followed?– Adequacy and completeness of records?

Investigator inspections: all centers - 2006

CDER: 379

CBER: 66

CDRH: 183

183

37966

Foreign n = 89Domestic n = 290

0%

5%

10%

15%

20%

25%

30%

Protocol Record AEs Consent Drug Acct

Foreign

Domestic

Clinical investigator deficienciesCDER inspections - FY 2006

Prevalence of OAI inspections (DSI Data)

Total number of FDA inspections

FY04 – FY06* = 1175

Total OAI cases = 31

Percent OAI = 3%

Total Inspected

Total OAI

*FY06 to date

Prevalence of OAI inspections (DSI Data)

Routine FDA inspections

FY04 – FY06* = 936

Total OAI cases = 2

Percent OAI = .6%

Directed FDA inspections

FY04 – FY06* - 239

Total OAI cases = 25

Percent OAI = 11%

Routine Inspections Total OAI

Directed Inspections Total OAI

*FY06 to date

Complaints to the Division of Scientific Investigations (DSI)

• The number of complaints about clinical investigators and clinical trials continues to increase

• DSI encourages such reporting (new Electronic Complaint Form)

• Follow-up on complaints is of vital strategic importance– Real-time follow-up– Public protection – Public confidence

What are they complaining about?

• Informed Consent Issues

• Falsification• Failure to report

adverse events• Failure to follow the

protocol• Inadequate Records• Qualifications of

persons performing physicals

• Failure to get IRB approval, report changes in research

• Failure to follow FDA regulations

• Drug accountability• Recruitment Practices• Poor Supervision• No active IND• Violations of GLP

regs• Monitoring practices• Blinding• Charging for the test

article• Misleading

advertisements

Complaints received: 1992-2006

0

50

100

150

200

250

300

350

4001992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

2005

2006

CI “for cause” inspection assignments(CDER, FY 1992 – 2005*)

0

20

40

60

80

100

120 9293949596979899FY00FY01FY02FY03FY04FY05

*FY05 through 10/05

BIMO inspects more than just clinical investigators

• Sponsors and monitors

• IRBs

• GLP

• Bio-equivalence

BIMO inspections completed

*FY06 to date

627678

549556

683 690 723 692657

580

0

100

200

300

400

500

600

700

800

FY97FY98

FY99FY00

FY01FY02

FY03FY04

FY05

*FY06

S-MCIIRBBIOEQGLP

BIMO warning letters by year and type

0

5

10

15

20

25

2001 2002 2003 2004 2005

CI

Sponsor

IRB

GLP

0

5

10

15

20

25

30

35

40

45

2004-41

2005-36

2006-28

2007-16

*Thru May 2007

2004 2005 2006 *2007

All GCP warning letters by year (2004 – May 2007)

Warning letter observations for investigators, including sponsor-investigators (Total 2004 – May 2007)

0 50 100 150

Regulatory Approval

Human Subj (not incl IC)

Informed Consent

Protocol Deviations

Records / Reports

Adverse Events

Invest. Deficiencies

Sponsor Deficiences

False Data

Monitoring

Misc

Sponsor FDA warning letters

• Sponsors are more likely to have problems with monitoring, which makes sense

• Records and reports still a frequent observation (and an easy target for FDA)

• Not surprisingly, FDA more likely to target investigators with human subject violations, such as IRB and IC violations, because these are investigator responsibilities

Warning letter observations for sponsors (Total 2004 – May 2007)

0 10 20 30

Regulatory Approval

Human Subj (not incl IC)

Informed Consent

Protocol Deviations

Records / Reports

Adverse Events

Invest. Deficiencies

Sponsor Deficiences

False Data

Monitoring

Misc

Total warning letters for drugs, devices, and biologics (Total 2004 – May 2007)

0

10

20

30

40

50

60

70

80

90

100

Drug Biologic Device

FDA warning letters as focused on drugs vs. devices. vs. biologics

• Many, many more device letters

• Wide difference in number of letters makes it difficult to make apple-to-apple comparisons.

• However, relatively more observations in device warning letters relating to:– Sponsor deficiencies– Monitoring

Warning letter observations for drugs, devices, and biologics (Total 2004 – May 2007)

0

20

40

60

80

100

120

140

160Regulatory Approval

Human Subj(not incl IC)

Informed Consent

Protocol Deviations

Records/Reports

Adverse Events

Investigator Deficiencies

Sponsor Deficiencies

False Data

Monitoring

Misc.

Biologic Device Drug

Sponsor’s experience defending studies in litigation

• University of Pennsylvania Study (1999) – Death of 18 year-old Jesse Gelsinger in a

gene therapy trial for the treatment of an inherited liver disease resulted in an undisclosed settlement and U.S. Senate hearings

– Study approval required termination of the trial if patients suffered serious side effects

– Researchers failed to alert FDA to reports of earlier patients whose liver damage warranted termination

– The level of ammonia in Gelsinger’s liver should have excluded him from participating in the trial

Sponsor’s experience defending studies in litigation

Johns Hopkins University (2001)– Death of 24 year-old Ellen Roche in a

federally funded lung physiology study on asthma treatment resulted in an undisclosed settlement

– FDA alleged inadequate oversight by the IRB

– Supervising physician failed to perform a sufficient literature search on the dangers of the chemical under investigation.

Studies examining weaknesses

• 1996 GAO study suggesting that Federal oversight is lax

• 1999 NYT “Research for Hire. A Doctor’s Drug Studies Turn into Fraud.”

• 2000 Washington Post “The Body Hunters.”• 1999-2001 National Bioethics Advisory

Commission Report on research compliance

• 2001 GAO report on progress in strengthening protections

• 2005 Office of Research Integrity/HHS Annual Report

Studies examining weaknesses

• Clinical Trial Web Sites: A Promising Tool to Foster Informed Consent (OEI-01-97-00198 May 2002)

• FDA Oversight of Clinical Investigators (OEI-05-99-00350 June 2000)

• Institutional Review Boards: The Emergence of Independent Boards (OEI-01-97-00192 June 1998)

• Institutional Review Boards: Their Role in Reviewing Approved Research (OEI-01-97-00190 June 1998)

• Institutional Review Boards: A Time for Reform (OEI-01-97-00193 June 1998)

• Institutional Review Boards: Promising Approaches (OEI-01-98-00191; 6/98)

• Protecting Human Research Subjects: Status of Recommendations (OEI-01-97-00197; 4/00)

• Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research (OEI-01-97-00195 June 2000)

• Recruiting Human Subjects: Sample Guidelines for Practice (OEI-01-97-00196; 6/00)

• The Globalization of Clinical Trials: A Growing Challenge in Protecting Human Subjects (OEi-01-00-00190; 09/01)

• Recruiting Human Subjects: Pressures in Industry-Sponsored Clinical Research (OEI-01-97-00195; 6/00)

Summary of hot spots

• Investigator financial conflicts and interests, including consulting relationships

• Reporting requirements, including adverse event reporting

• Conducting studies outside the U.S. and harmonizing GCP obligations

• Enforcement focusing on device studies– Device regulatory environment becoming

more like drugs

Topics1. Importance of quality assurance

2. Overview of risk management approach

3. Good Clinical Practices

4. GCP experience

5. Quality and risk management techniquesA. Quality Management systemB. Procedures and agreementsC. TrainingD. MonitoringE. AuditingF. Metrics

Quality Management System, definition based on ISO 9000

• A set of interacting elements established to direct and control an organization with regards to quality

• QMS is a tool to establish and continuously & consistently achieve quality objectives based on customers’ requirements.

• In clinical research these objectives are:– Compliance with ethical, regulatory and

GXP standards– Credibility and reliability of clinical data

Standard components of QMS in clinical research

Quality Assurance

Quality Control

Trialprotocol

Trialreport

Collection & analysis of data

Training Procedures

Procedures: Investigator

• Trial-related instructions, protocol, CRFs, etc. – usually provided by the Sponsor

• Investigator / Research Site may have own internal procedures: e.g., procedures for financial agreements, trial management, investigational medicinal product handling

• Ethics committee procedures• Laboratory procedures

Procedures: Sponsor

• High level documents, e.g. Policies & Guidelines describe standards / customer requirements that the sponsor is going to comply with

• SOPs & Working Instructions detail how these standards and requirements will be implemented in core activities within the clinical research process– The ‘every day work’

Procedures: Sponsor SOPs

• SOPs may include the following sections:– Approval Process SOPs– Subject Recruitment SOPs– Advertising SOPs– Trial Monitoring SOPs– Record Keeping SOPs– Data and Safety Monitoring Board

SOPs– Adverse Event Reporting SOPs

Procedures: Benefits

• Clear instructions on what should be done, when and by whom, plus specification of required inputs & outputs

• Training tool• Maintain consistency of work and

consistency in achieving quality objectives

• Facilitate change management (may be easily updated & reviewed when requirements change)

Other written controls: Contracts

• In addition to being required in certain instances, clinical trial agreements set expectations and establish obligations for all parties– e.g.,– Sponsor– Institution– Investigator– CRO– SMO– Others

• Make the budget and payment schedule part of the agreements and review just as you would other provisions

• Be cognizant of institution and investigator SOPs that may affect their ability to agree to certain provisions

Training

• Sponsor’s staff must be trained before being delegated any tasks

• Sponsor is responsible for providing trial-related training to investigators: Investigator’s Meetings, initiation visits, GCP courses

• Investigator is responsible for training his personnel

• Training records, CVs – are required as evidence of training & qualifications

Training

• Many folks at the sponsors, at the sites and at contractors need to be trained

• Common shortcoming: many training materials are developed in a vacuum– Not validated with input from real

world setting– Therefore not effective or robust

enough• Be sure to measure effectiveness

of training

Quality Control

• ISO: activities & techniques applied to ensure that products consistently fulfill requirements

• Clinical Research: systematic checks on the compliance of the trial process & reliability and credibility of data– Performed at every step of the clinical

trial process– Applied to each stage of data

handling.

Quality Control

trial protocol

collectionof data

poolingof datain the

database

analysis trialreport

Sponsorapproval &

sign off

Monitoring of investiga-tional sites

Proof-reading, validation,

generation of queries

Identification of non-PPT

cases

IEC approvalanalysis of outlier data

variability & trends

approval & sign-off

Monitoring

• Two functions that sound alike– Data Monitoring Committee– Site Monitors

• They must work together

• Requirement for written monitoring procedures (21 CFR 812.25(e))

Site monitor responsibilities

a) Verifying that the staff and facilities, including laboratories and equipment, are adequate to safely and properly conduct the trial and these remain adequate throughout the trial period.

b) Verifying, for the investigational product, its proper handling etc.c) Verify that all modifications to the study plan have been

submitted to FDA and IRB prior to implementation.d) Verify that all modifications to the study plan have been

approved by IRB prior to implementation.e) Verifying that the investigator follows the approved protocol and

all approved amendments, if any.f) Verifying that written informed consent was obtained before

each subject's participation in the trial.g) Ensuring that the investigator's trial staff is adequately informed

about the trial.h) Verifying that the investigator and the trial staff are performing

the specified trial functions in accordance with the protocol and the investigator has not delegated these functions to unauthorized individuals.

i) Verifying that the investigator is enrolling only eligible subjects.

Site monitor responsibilities

j) Reporting the subject recruitment rate.k) Verifying that source data/documents and other trial records are

accurate, complete, kept up-to-date, and maintained.l) Verifying that the investigator provides all the required reports,

etc., and that these documents are accurate, complete, timely, legible, dated, signed, and identify the trial.

m) Checking the accuracy and completeness of the CRF entries, source data/documents, and other trial-related records against each other.

n) Determining whether all adverse events are appropriately reported within the time periods required by GCP, the protocol, the IRB, and the applicable regulatory requirements.

o) Determining whether the investigator is maintaining the essential documents.

p) Communicating deviations from the protocol and the applicable regulatory requirements to the sponsor and investigator and taking appropriate action designed to prevent recurrence of the detected deviations including reporting deviations to IRB and FDA.

q) Verify that the final study report is accurate    

Data Safety and Monitoring Board (DSMB)

• A.K.A., Data Monitoring Committee, Data and Safety Monitoring Committee

• Committee set up to oversee safety monitoring of the clinical trial

• Reviews the accumulating data to detect evidence of early dramatic benefit or harm for patients while the clinical trial is in progress

• Functions of DSMB should be clearly defined prior to initiating the study

Potential functions of DSMB

• Review safety data

• Review efficacy data

• Review trial conduct

• Review external data (e.g., related studies)

• Issue recommendations

• Keep meeting records (e.g., minutes and reports)

Reasons for DSMB oversight

• Protect patients’ rights

• Ensure that risks are minimized

• Ensure data integrity

• Terminate a trial based on interim data if safety concerns arise or objectives have been met

Quality Assurance

• ISO: a set of activities to provide confidence that quality requirements will be fulfilled

• Clinical research: independent audits of all trial-related processes & functions– Performed by QA function not

involved in the research process (no conflict of interests)

– Assess efficiency of sponsors’ QC processes.

Quality Assurance audits

• Trial / project specific audits

• Systems audits– System: A selected process plus all

related activities, resources, organization, documents (including SOPs & records), facilities and equipment, e.g., Pharmacovigilance, Data Management

QA, trial specific audits

trial protocol

collectionof data

poolingof datain the

database

analysis trialreport

audit of the study

protocol

audits at trial sites

audit of trial database

audit of trial report

audit of CRF, IB

audit of graphs, tables &

stats

QA, systems audits

Collection & analysis of data

audit of computerized data collection systems (validation audits)

audit of monitoring

system

audit of IP management & distribution

system

audit of document

management & archiving

audits of central lab & other

service providers

audit of sponsor’s pharmacovigilance

system

Benefit of QMS

It supports continuous quality improvement

ACT PLAN

CHECK DO

implementrecommendations

QA audits

QC activities

development of trial protocol & instructions

training

in line with SOPs

clinical trial process

Using metrics in clinical trial quality management

• What gets measured, gets done– What does not get measured, may not get

done• Two important types of metrics

– For yesterday and today• For example, historical financial

performance– For tomorrow

• For example, how much are we improving (i.e., a rate of change)?

• Where are we in important skills and abilities?

Questions and Discussion