Harrison Clinical Research Monitoring of Clinical Trials - Quality Management from a CRO s Perspective www.harrisonclinical.com 1 17Sep2009
Overview: Monitoring of Clinical Trials 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 noncompliance www.harrisonclinical.com 2 17Sep2009
Discovering and Developing New Medicines Over $ 1 billion on average 1) depending on therapeutic category Clinical trials account for 40% of total R&D costs 2) 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 same 1) 12-15 years to market, only 5-8 years before patent expires 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 www.harrisonclinical.com 3 17Sep2009
Desired Outcome of Clinical Trials (Sponsor Perspective) 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 www.harrisonclinical.com 4 17Sep2009
Quality Management Coordinated activities to direct and control an organisation with regard to quality (ISO 9000:2005) www.harrisonclinical.com 5 17Sep2009
Compliance Adherence to all the trial-related requirements, GCP requirements, and the applicable regulatory requirements (ICH-GCP 1.15) www.harrisonclinical.com 6 17Sep2009
Relevant Legislation and Guidelines 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 www.harrisonclinical.com 7 17Sep2009
Sponsor vs. Contract Research Organization Definition Sponsor : An individual, company, institution, or organization which takes responsibility 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 15 th 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. www.harrisonclinical.com 8 17Sep2009
Reasons to Involve CROs Sponsor purchases as needed: Resources (time, and background of persons) Established relationships (sites, suppliers) www.harrisonclinical.com 9 17Sep2009
Who is Responsible for Ensuring Compliance A sponsor may transfer any or all of the sponsor s trialrelated 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) www.harrisonclinical.com 10 17Sep2009
Purpose of Monitoring According to GCP 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) www.harrisonclinical.com 11 17Sep2009
Qualifications of a Monitor According to GCP Monitors should be appointed by the sponsor Monitors should be appropriately trained and have the scientific and/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) www.harrisonclinical.com 12 17Sep2009
How Good are Your Monitors 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 www.harrisonclinical.com 13 17Sep2009
Ensure Compliance Site Selection 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 www.harrisonclinical.com 14 17Sep2009
Ensure Compliance Selection Challenges If potential problems are noted, Monitor should suggest possible strategies 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!! www.harrisonclinical.com 15 17Sep2009
Ensure Compliance Prior to the Study 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 www.harrisonclinical.com 16 17Sep2009
Ensure Compliance Critical Steps Pre Study Visit (potential for non-compliance) Initiation Visit (potential for non-compliance) Monitoring Visit (potential for non-compliance and actual noncompliance) First Monitoring Visit Monitoring frequency Time allowed for monitoring Close Out Visit www.harrisonclinical.com 17 17Sep2009
Training of Investigator for Compliance 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 www.harrisonclinical.com 18 17Sep2009
COMPLIANCE Benefits Risks Assessment of Investigator Performance is a Continual Process Benefits B B B B B BB RRR Risks www.harrisonclinical.com 19 17Sep2009
Ensure Compliance During the Study (ICH-GCP 5.18.4) 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) www.harrisonclinical.com 20 17Sep2009
What You See and What You Have to Consider Symptoms: paper trail Root cause: Lack of involvement Poor training Inexperience Limited system or procedures Intent: Repeated Deliberate www.harrisonclinical.com 21 17Sep2009
Able to identify problems. Effective process to correct and prevent. Noncompliance Able to identify problems. Process to correct. Ineffective process for prevention. Able to identify problems. Ineffective process for correction. Unable to identify problems. No process for correction. www.harrisonclinical.com 22 17Sep2009
Non-Compliance Investigation Worksheet Microsoft Word Document www.harrisonclinical.com 23 17Sep2009
Non-compliance, Serious Breach and Suspicion of Misconduct 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 the occurrence of such intentional recording, reporting, or withholding as a result of gross negligence. www.harrisonclinical.com 24 17Sep2009
Non-Compliance: Level I 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... www.harrisonclinical.com 25 17Sep2009
Non-Compliance: Level II 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... www.harrisonclinical.com 26 17Sep2009
Non-Compliance: Level III 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... www.harrisonclinical.com 27 17Sep2009
Actions to be Taken by Monitor in Case of Noncompliance 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 www.harrisonclinical.com 28 17Sep2009
Actions to be Taken by Management 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 www.harrisonclinical.com 29 17Sep2009
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 www.harrisonclinical.com 30 17Sep2009
What People See is Different Monitor s view Management s view www.harrisonclinical.com 31 17Sep2009
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) www.harrisonclinical.com 32 17Sep2009
Umbrella of Protection Achieve compliance through: CA EC Subject Consumer Sponsor Clinical Investigator Confirmed accepted rules Defined responsibilities Sufficient resources Knowledgeable team Overlapping systems Common effort www.harrisonclinical.com 33 17Sep2009
Harrison Clinical Research Thank You www.harrisonclinical.com 34 17Sep2009