monitoring of clinical trials - quality management from a ... · monitoring of clinical trials -...

www.harrisonclinical.com 1 17Sep2009

Harrison Clinical Research

Monitoring of Clinical Trials -

Quality Management

from a CRO’s Perspective


1. Discovering and developing new medicines

2. Relevant laws and guidelines

3. CRO, Sponsor, and division of responsibilities

4. Ensuring compliance

5. Measures to be taken in case of non-compliance

Overview: Monitoring of Clinical Trials


► Over $ 1 billion on average1) depending on therapeutic category

► Clinical trials account for 40% of total R&D costs2)

► Pharma’s collective investment in R&D increased from $ 2 billion in 1980 to $ 43 billion in 2006 whereas the number of drugs approved by the FDA in 1980 and in 2006 was roughly the same1)

► 12-15 years to market, only 5-8 years before patent expires

Discovering and Developing New Medicines

1) Garnier, J.-P. “Rebuilding the R&D Engine in Big Pharma”. Harvard Business Review, May 2008.

2) Kermani, F., Narayan-Dubois, C. “Thinking ahead for effective clinical trials”. Bioentrepreneur, February 22, 2005. doi:10.1038/bioent844


► Results that are suitable to support the submission of a dossier based on which marketing authorization will be granted swiftly by regulatory authorities

► Prerequisites for this:Timely capture, analysis and reporting of compliant data

Desired Outcome of Clinical Trials (Sponsor Perspective)


“Coordinated activities to direct and control an organisation with regard to quality”

(ISO 9000:2005)

Quality Management


“Adherence to all the trial-related requirements, GCP requirements, and the applicable regulatory requirements”

(ICH-GCP 1.15)

Compliance


► AMG, 15th Novell, effective July 2009,

► Decree on GCP Compliance, effective August 2004

► ICH-GCP, effective June 1996

► EU Directive 2001/20/EG, effective April 2001

► EU Directive 2003/94/EG, effective October 2003

► EU Directive 2005/28/EG, effective April 2005

Relevant Legislation and Guidelines


Definition “Sponsor”:

“An individual, company, institution, or organization which takesresponsibility for the initiation, management, and/or financing of a clinical trial.” (ICH-GCP 1.53)

“Sponsor ist eine natürliche oder juristische Person, die

die Verantwortung für die Veranlassung, Organisation und

Finanzierung einer klinischen Prüfung bei Menschen

übernimmt.” (AMG 15th Novell, §4(24))

Definition “CRO”:

“A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions.” (ICH-GCP 1.20)

►Both Sponsor and CRO are subject to the same laws, regulations and standards.

Sponsor vs. Contract Research Organization


Reasons to Involve CROs

Sponsor purchases as needed:

► Resources (time, and background of persons)

► Established relationships (sites, suppliers)


► “A sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a CRO, but the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.”(ICH-GCP 5.2.1)

► CRO must be authorized by sponsor in writing to undertake certain trial-related activities. Any such activities not specifically transferred to the CRO are retained by the sponsor. (ICH-GCP 5.2.2 / 5.2.3)

Who is Responsible for Ensuring Compliance


► To protect the rights and well-being of subjects

► To ensure that the reported trial data are accurate, complete and verifiable from source documents

► To ensure that the conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP and with the applicable regulatory requirement(s)

(ICH-GCP 5.18.1)

Purpose of Monitoring According to GCP


► Monitors should be appointed by the sponsor

► Monitors should be appropriately trained and have the scientificand/or clinical knowledge needed. Qualifications should be documented.

► Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, GCP, and the applicable regulatory requirements.

(ICH-GCP 5.18.2)

Qualifications of a Monitor According to GCP


► Adequately trained?

� Initial training and competent to conduct PSV, SIV, MV, COV

� Continuous training following e.g. ISO 10015

► Empowered and supported by management to secure compliance?

► Adequate time on site?

► Noncompliance

� Identification

� Investigation

� Communication

� Resolution

How Good are Your Monitors


► Determination of suitability of proposed study center:

� Investigator with adequate qualifications

� Investigator with adequate resources

� Available facilities are sufficient and adequate

� Storage conditions for IMP are acceptable

� Recruitment potential adequate

► Ensuring that study site personnel are adequately informed about the trial, receive Investigator’s Brochure and other relevant documents

Ensure Compliance – Site Selection


► If potential problems are noted, Monitor should suggest possiblestrategies to ensure compliance:

� Additional training

� More frequent monitoring visits

� Request additional site personnel

� Flying nurse

� Attendance of monitor prior to and/or during the first randomization visit in order to ensure eligibility of patient and to provide any assistance necessary.

► These measures should be discussed with sponsor and agreed

upon before center is included in the trial !!

Ensure Compliance – Selection Challenges


► Do not waive Pre Study Visits

► Pre Study Visits to be conducted by experienced CRAs

► Adequate time on site for Pre Study Visits

► Confirm Principal Investigator’s supervisory responsibilities

► Announce that investigator performance is assessed on an ongoing basis

Ensure Compliance – Prior to the Study


► Pre Study Visit (potential for non-compliance)

► Initiation Visit (potential for non-compliance)

► Monitoring Visit (potential for non-compliance and actual non-compliance)

� First Monitoring Visit

� Monitoring frequency

� Time allowed for monitoring

► Close Out Visit

Ensure Compliance – Critical Steps


► Ensure investigator understands his/her responsibility for compliance at the Pre Study Visit, reiterate at the Site Initiation Visit and continuously during the Monitoring Visit

► Provide tools and information to assure understanding and continued compliance

► Timely involvement of the investigator in any identified noncompliance to assure correction and prevention

Training of Investigator for Compliance

Assessment of Assessment of

Investigator Investigator

Performance is a Performance is a

Continual ProcessContinual Process

B B B BB B BB

RRR

Benefits

Benefits

Risks

Risks

COMPLIANCE



► Regular monitoring visits

► Review of source data and documented trial data

► Review of subject eligibility and documentation of informed consent

► Review of IMP storage, administration, and documentation

► Review of AEs

► Review of ‘Essential Documents’ in site file

► Providing timely monitoring reports to the investigator and sponsor

AND

► Reporting of any deviation/non-compliance noted, any actions taken as a result of non-compliance and any measures suggested for securing future compliance(ICH-GCP 5.18.6)

Ensure Compliance During the Study (ICH-GCP 5.18.4)

Symptoms: paper trail

Root cause:

�Lack of involvement

�Poor training

�Inexperience

�Limited system or procedures

Intent:

�Repeated

�Deliberate

What You See – and What You Have to Consider


Noncompliance

Noncompliance

Noncompliance

Noncompliance

Unable to identify problems. Unable to identify problems. Unable to identify problems. Unable to identify problems. No process for correction.No process for correction.No process for correction.No process for correction.

Unable to identify problems. Unable to identify problems. Unable to identify problems. Unable to identify problems. No process for correction.No process for correction.No process for correction.No process for correction.

Able to identify problems. Able to identify problems. Able to identify problems. Able to identify problems. Ineffective process for correctionIneffective process for correctionIneffective process for correctionIneffective process for correction.

Able to identify problems. Able to identify problems. Able to identify problems. Able to identify problems. Ineffective process for correctionIneffective process for correctionIneffective process for correctionIneffective process for correction.

Able to identify problems. Process to Able to identify problems. Process to Able to identify problems. Process to Able to identify problems. Process to correct. Ineffective process for prevention.correct. Ineffective process for prevention.correct. Ineffective process for prevention.correct. Ineffective process for prevention.

Able to identify problems. Process to Able to identify problems. Process to Able to identify problems. Process to Able to identify problems. Process to correct. Ineffective process for prevention.correct. Ineffective process for prevention.correct. Ineffective process for prevention.correct. Ineffective process for prevention.

Able to identify problems. Able to identify problems. Able to identify problems. Able to identify problems. Effective process to correct and prevent.Effective process to correct and prevent.Effective process to correct and prevent.Effective process to correct and prevent.

Able to identify problems. Able to identify problems. Able to identify problems. Able to identify problems. Effective process to correct and prevent.Effective process to correct and prevent.Effective process to correct and prevent.Effective process to correct and prevent.


Non-Compliance Investigation

Worksheet

Microsoft Word

Document



► Non-compliance: Lack of adherence to clinical study related regulations and requirements

► Serious Breach: A breach in the conditions and principles of GCP, or the trial protocol, which is likely to effect to a significant degree the safety or physical or mental integrity of subjects of the trial or the scientific value of the trial regardless of whether it is persistent, accidental or deliberate

► Misconduct: The intentional recording and/or reporting of fabricated, false, or misleading information, or data pertaining to a clinical study, as well as withholding of reportable information or data, or theoccurrence of such intentional recording, reporting, or withholding as a result of gross negligence.

Non-compliance, Serious Breach and Suspicion of Misconduct


► Level I: Random Incidents of Non-Compliance

Examples:

� Missing, incomplete or inconsistent source documentation

� Delayed review of test results or laboratory reports

� Prohibited concomitant medication

� Improper medication storage

� ...

Non-Compliance: Level I


► Level II: Repeated Incidences of Non-Compliance, Serious Breach or Suspicion of Misconduct

Examples:

� Repeated Level I non-compliance

� AE data significantly different from other sites

� Informed consent not obtained correctly

� ...

Non-Compliance: Level II


► Level III: Misconduct or Refusal to Correct Non-Compliance

Examples:

� Refusal to correct non-compliance

� Forged documents

� Coercion of subjects or staff

� Consistent lack of Principal Investigator’s personal involvement in the study

� ...

Non-Compliance: Level III


► Identify non-compliance issues

► Investigate non-compliance (root cause, intent)

► Communicate non-compliance to investigator, site staff, to PM

► Suggest corrective and preventive action (CAPA)

► Document non-compliance, any action taken, and all CAPA measures suggested in forms/MVR and follow-up letters

► Evaluate implementation of corrective actions

► Document successful resolution of (repeated) non-compliance OR re-document unsuccessful resolution, discuss again with investigator and re-implement CAPA measures...

► IF NECESSARY, escalate to next non-compliance level

Actions to be Taken by Monitor in Case of Non-compliance


► PM to discuss possible further actions with:

� Sponsor (report to authorities?)

� Quality Management (audit?)

► Convene Non-Compliance Review Committee

� Representatives of: Quality Management, Company Management, Operational Department involved (e.g. Clinical Operations)

� Review and document all action thus far

� Action plan, possibly including:

� Report to authorities/EC

� Audit

� Discontinuation of investigator’s participation

� Review by biometrics to determine validity of data collected

� Legal action

Actions to be Taken by Management


Learn from Non-compliances

► Non-compliance involves

� Investigational medicinal product

� Subjects safety, rights, welfare

� Data integrity

► Non-compliance Subtype (example)

� IMP deficiencies

� IMP related documentation deficiencies

� IMP used by someone not authorised to receive

� IMP improper storage/access

► Evaluate number and level of non-compliances

► Feed-back the information and spend the resources where they are needed

Monitor’s view Management’s view

What People See is Different


What is the Role of Management

► Monitor the trial at the study level (not site level)

► Assure sufficient budget, time, and resource

► Stop the Process if compliance cannot be secured

� Stop shipment of additional IMP

� Terminate investigator participation in trial

� Report to EC / CA

►Assure organisation is controlled and directed towards defined quality level (compliance)



Umbrella of Protection

Clinical

Investigator

Subject

Consumer

CA Sponsor

EC

Achieve compliance through:

► Confirmed accepted rules

► Defined responsibilities

► Sufficient resources

► Knowledgeable team

► Overlapping systems

► Common effort

Harrison Clinical Research

Thank You
