Boehringer Ingelheim & Human Pharmacology Center

Transcription

1 Boehringer Ingelheim & Human Pharmacology Center Impact factors for quality in early phase clinical trials Hermann Angele Dr. Birgitta Schieder Agenda 1- Regulations - Definition of "Quality" 2- Qualification of personnel (e.g. PI, study team) 3- Documentation and Archiving (e.g. IC, CRF, ISF (Essential Documents)) 4- Equipment and system validation 5- Monitoring 6- Non compliances and appropriate actions 7- Supervision of clinical trials, sponsor responsibility AGAH - H. Angele / B. Schieder - Nov 2016 V1.0 2 AGAH QM Workshop November No. 1 1

2 Human Pharmacology Center Importance of Human Pharmacology Early Phase Human Pharmacology focussed on early go/no-go decisions based on Safety & tolerability Pharmacokinetics / Pharmacodynamics Critical interactions (drug, food) Extended Phase Human Pharmacology thorough characterisation following early Phase e.g. QT effects, formulations, DDI Trial Population Healthy Volunteers Cannot be expected to derive (therapeutic) benefit from the study AGAH - H. Angele / B. Schieder - Nov 2016 V Regulations EU Clinical Trial Directive (EC) No. 2001/20/EC / Clinical Trial Regulation EU No. 536/2014 ICH GCP: GUIDELINE FOR GOOD CLINICAL PRACTICE E6(R1) Current Step 4 version dated 10 June 1996 GCP V: Verordnung über die Anwendung der Guten Klinischen Praxis bei der Durchführung von klinischen Prüfungen mit Arzneimitteln zur Anwendung am Menschen (GCP-Verordnung - GCP-V) abpi Guidelines for phase 1 clinical trials edition First in Human Studies: Points to Consider in Study Placement, Design and Conduct 2011 edition Guidance for Industry CGMP for Phase 1 Investigational Drugs - July 2008 CGMP AGAH - H. Angele / B. Schieder - Nov 2016 V1.0 4 AGAH QM Workshop November No. 1 2

3 1. Regulations Concept paper on the revision of the 'Guideline on strategies to identify and mitigate risks for first-in-human clinical trials with investigational medicinal products' EMA/CHMP/446302/2016 Product-Specific Bioequivalence Recommendations; Draft and Revised Draft Guidance for Industry - product-specific guidance on the design of BE studies to support abbreviated new drug applications (ANDAs). "Bioequivalence Recommendations for Specific Products (IDRAC )' FDA: Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers 2005 AGAH - H. Angele / B. Schieder - Nov 2016 V Regulations Medizinproduktegesetz in der Fassung der Bekanntmachung vom 7. August 2002 (BGBl. I S. 3146), das zuletzt durch Artikel 2 Absatz 80 des Gesetzes vom 07. August 2013 (BGBl. I S. 3154) geändert worden ist Verordnung über klinische Prüfungen von Medizinprodukten DIN EN ISO 14155:2011 Klinische Prüfung von Medizinprodukten an Menschen Gute klinische Praxis AGAH - H. Angele / B. Schieder - Nov 2016 V1.0 6 AGAH QM Workshop November No. 1 3

4 1. Definition "quality" The totality of features and characteristics of a product or service that bears on its ability to satisfy stated or implied need (ISO 8402) Quality characteristics: inherent characteristics of a product, process or system related to requirement (ISO 9000:2015) Quality: degree to which a set of inherent characteristics fulfils requirements (ISO 9000:2015) when you meet the requirements.. AGAH - H. Angele / B. Schieder - Nov 2016 V Qualification of personnel Specification of Qualification The basic regulations GCP, GCP-V, AMG indicate Investigator should be qualified by education, training, and experience Trial staff should be appropriately qualified Ethics committee to assess investigator s qualification and suitability of the trial site. No substantial specification, except AMG (Investigator -> two years experience) Required qualification depends on the respective trial and it s specific requirements the delegated responsibilities the risk profile of a trial (-> healthy volunteers) Arranged emergency care processes AGAH - H. Angele / B. Schieder - Nov 2016 V1.0 8 AGAH QM Workshop November No. 1 4

5 2. Qualification of personnel cont. Early clinical phase units should Predefine requirements for professional qualification and experience Job profiles Ensure accredited investigator training (e.g. Curriculare Fortbildung BÄK, Grundlagenkurs für Prüfer) Role-based training curricula Ensure availability of certificates /training records SOP in place Ensure continuous process improvement Implement adequate tools / processes Promote continued education of staff Employee development AGAH - H. Angele / B. Schieder - Nov 2016 V Qualification of personnel cont. Estimate the human factor Successful trial conduct is teamwork Highly qualified, dedicated personnel is an important value Investments in appreciation and training of personnel will be paid back Medical- and GCP- knowledge is essential -> and should be accompanied by basic understanding of quality processes Robust on-site trial planning is essential -> a well-trained, committed study coordinator/study nurse is the key success factor AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 5

6 3. Trial Documentation and Archiving Documentation Trial Documentation Records in any form that describe or record methods, conduct, results of a trial, the factors affecting the trial, and the actions taken. (ICH-GCP 1.2.2) Purpose of trial documentation Based on essential documents (ICH-GCP 8.1) and entire trial documentation Sponsor and Investigator should be able to demonstrate Valid trial conduct Rights, safety and well-being of trial subjects was granted Adherence to trial protocol Integrity and traceability of trial data Compliance with GCP and applicable regulations -> Trial documentation should allow a retrospective reconstruction of the trial (including decision-making) AGAH - H. Angele / B. Schieder - Nov 2016 V Trial Documentation and Archiving cont. Documentation Good documentation practice ALCOA principles (Attributable, Legible, Contemporaneous, Original, Accurat) Well-organized filing enable monitoring, audit, inspection Ideally, trial records describe the issues in detail Essential documents state a minimum requirement only Two more sentences are better than one less Independent colleague should be able to explain the issues even years later AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 6

7 3. Trial Documentation and Archiving cont. Documentation Electronic trial documentation system In early phase units electronic trial documentation systems are an essential backbone for trial documentation and become more and more vital PRO s : Allow control of trial activities and processes Guide users through trial tasks Help to prevent mistakes (direct feedback) Ensure commenting on deviations Control allowed time windows Control currency of documents (e.g. correct IC- version) Support site-internal monitoring of trial activities (e.g. PI oversight) Provide electronic data transfer to sponsor (e.g. batch files ) Shorten monitoring effort AGAH - H. Angele / B. Schieder - Nov 2016 V Trial Documentation and Archiving cont. Documentation CON s for electronic trial documentation systems : Costs Validation efforts Maintenance efforts (changes in hardware / operating system) Poor flexibility (validation requirements) HPZ experience with running a e-trial Documentation System (ClinBase ) is very good 5 FDA inspections in a row without a single observation! Inspectors were very impressed by the system AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 7

8 3. Trial Documentation and Archiving cont. Archiving Various legal/administrative/ professional regulations potentially interfere (MPG, Röntgen und Strahlenschutzverordnung, MBO-Ä, StrlSchV, RöV, TPG, GenTG, GentAufzV, 2001/20/EG, 2005/28/EG,..) Consider different requirements Archive-conditions depend on media Paper/Electronic storage media/microfilm/data base Document relationship may cause different archive-locations Related to single trial/several trials? Trial independent documents Retrieval, prompt delivery (in case of inspections) Sounds simple but is really a challenge! External service providers Data protection regulations to be kept Medical confidentiality to be kept AGAH - H. Angele / B. Schieder - Nov 2016 V Trial Documentation and Archiving cont. Archiving General Trial documentation should be prevented from corruption and damage over the entire storage period (Site 15a 25a, Sponsor 30a) Minimum requirements for archive rooms Lockable door Fire protection Emergency action plan Alarm system connected to security personnel Accessible for a limited number of authorized personnel only Log book to document personnel entries / stock, removal of documents Stable environmental conditions (paper 14 to 18 C / 35 to 50% humidity) No electric devices, printers, scanners Protection from direct sun light, flooding, pests t.b.c. AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 8

9 4. Validation of equipment Validation/Qualification of equipment is an elementary component of a professional clinical trial facility. It proofs that rooms/equipment/systems/methods Are suitable for their intended use Ensure quality of the generated GCP- relevant data V - model as common approach to validation activities Validation Determination Planning for Implementation and Validation Changes/ Improvements Retirement Operational Use Specification and Design Phase Verification (Qualification Phase System Build and Installation AGAH - H. Angele / B. Schieder - Nov 2016 V Validation of equipment cont. Validation activities Validation Determination Define the needed extent of validation activities User requirements Describe what the user wants the system to do Indicate the functional, operational and data requirements CFR part 11 compliance assessment Do CFR part 11 or other regulations apply to the equipment? Categorize equipment and decide if and to what extent validation is needed System allows software-access -> Complete validation GCP-data measured (e.g. Blood pressure device) -> Correct Function should be assured by detailed qualification measures GCP-data measured, setting cannot be changed (e.g. Alcometer) Periodic calibration, STK, MTK only AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 9

10 4. Validation of equipment cont. Validation activities Validation Master Plan high-level structure for the entire facility, Equipment list Risk Based Approach, Risk Assessment Evaluate risks (subject safety, data quality) Conclude depth of validation approach, determine degree of testings Validation Plan Define validation outcomes, roles/responsibilities, documentation, approval Installation/Qualification, Operational use Documented evidence (e.g. tests, acceptance criteria), documented executions (Installation-, Operational-, Performance Qualification) Periodic Review, Change Control Program, Problem Handling, CAPA Retirement -> Document archival, equipment disposal AGAH - H. Angele / B. Schieder - Nov 2016 V Monitoring in Human Pharmacology Trials Sponsor is responsible to implement quality assurance and quality control systems Monitoring is one instrument for QA/QC Purpose of monitoring Verify that the rights and well-being of human subjects are protected Verify that reported trial data are accurate, complete, and verifiable from source Verify compliant trial conduct (adherence to protocol, GCP, applicable regulations) Monitor s responsibilities are wide spread and extensive. They should be Appropriately trained, have clinical/scientific knowledge Thoroughly familiar with investigational product, protocol, informed consent form sponsor s SOPs, GCP, applicable regulatory requirement(s) To meet all requirements, monitoring should be guided by procedural documents. AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 10

11 5. Monitoring in Human Pharmacology Trials cont Specifics of human pharmacology trials Specialized trial facilities & Standardized, qualified equipment focus and prioritize monitoring on specific topics Numerous site staff time consuming checks of delegation log and staff list Elaborate trial progress, plenty of data, significant number of screenings, inclusions, first dosing within a few days plan sufficient, contemporary on-site visits attend the first relevant trial activities on-site Consider the details (PK/PD-data) and keep the big picture (recurrent ISF check) Healthy subjects are exposed to trial related risks but don t have any therapeutical benefit Highest demand on ethical aspect and subject safety No compromise accepted with respect to In-/Exclusion criteria AGAH - H. Angele / B. Schieder - Nov 2016 V Non compliances and appropriate actions Definitions Corrective Action Preventive Action (CAPA): Activities that result in the systematic investigation of non-compliances (= deviations) in an attempt to prevent their recurrence (Corrective Actions) or to prevent occurrence (Preventive Actions). Correction: Action to eliminate or limit the impact of a detected non-compliance or undesirable situation. Corrective Action: Action to eliminate the root cause of a detected non-compliance or other undesirable situation; to prevent the recurrence of the non-compliance. Preventive Action: Action to eliminate the root cause of a potential non-compliance or other undesirable situation; to prevent the occurrence of a non-compliance. AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 11

12 6. Non compliances and appropriate actions ICH GCP 1.15 Compliance (in relation to trials): Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, and the applicable regulatory requirements Non-Compliance (BI) / deviation: Non-adherence to applicable legislation, regulatory requirements, or written procedures (e.g., SOP, Protocols, etc.) classification: Critical, Major, Minor, or Comments Critical: Conditions, practices, processes or events that violate applicable legislation, regulatory requirements, or written procedures, and either: o adversely affect the rights, safety or well-being of patients / subjects, or o adversely affect the quality and integrity of data or products or system(s) o demonstrate potential risk to public health or indicate suspected fraud or misconduct. AGAH - H. Angele / B. Schieder - Nov 2016 V Non compliances and appropriate actions Major: Conditions, practices, processes or events that violate applicable legislation, regulatory requirements or written procedures, and might either: Minor: Conditions, practices, processes or events that violate applicable legislation, regulatory requirements or written procedures, but does not either: AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 12

13 6. Non compliances and appropriate actions CAPA process Non-compliance occurred decide criticality conduct root cause investigation - develop - approve CAPA actions - implement Effectiveness check AGAH - H. Angele / B. Schieder - Nov 2016 V Non compliances and appropriate actions Where to find non-compliances (= deviations)? - daily work - internal audits - inspection readiness activities - authority inspections - lessons learned after a trial AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 13

14 6. Non compliances and appropriate actions Non-compliance example major - an AE headache was recorded on day -4 (13-SEP-2014) - the AE was treated by the subject in self-medication with Ibuprofen - concomitant medication Ibuprofen 400 mg was documented relating to the mentioned AE headache ( intake on day -4, 13-SEP-2014, 12 am); concomitant medication was not allowed - the AE ended on day -4 (13-SEP-2014) - the concomitant medication was not notified by the investigator, and subject was not excluded from further treatment, therefore exclusion criteria no. 16 was hurt - subject completed the trial without having any further AEs - Trial 1xxx.yz was conducted at CRO XYZ and LPO was on 16 DEC 2014 AGAH - H. Angele / B. Schieder - Nov 2016 V Supervision of clinical trials, sponsor responsibility Supervision, responsibility of the sponsor 1. Site selection, site feasibility (internal vs. external) 2. Vendor selection 3. Site qualification site quality management 4. Vendor qualification vendor quality management 5. Responsible Sponsor trial function 6. CRA (Clinical Research Associate) 7. Quality unit AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 14

15 7. Supervision of clinical trials, sponsor responsibility partnership with vendors: vendor qualification assessment, quality agreement, detailed deliverables, expectations, timelines, milestones, responsibilities, KPIs. vendor oversight tools, like: regular meetings incl. meeting minutes, action plans, telephone calls, co-monitoring, quality oversight plans, QMA (Quality Management Agreements), trackers, questionnaires, escalation channels and defined communication pathways for issues, non-compliances, CAPAs, yearly or bi-annual documented assessment of vendors. assessing quality, trends, quality performance of vendors (KPIs, NC, CAPA, audits, recalls, complaints, questionnaires from purchasing or business assessments) Risk base approach: Depending on the criticality of the vendor or the criticality of the service define shorter or longer review cycles or deeper or lower assessments AGAH - H. Angele / B. Schieder - Nov 2016 V Questions AGAH - H. Angele / B. Schieder - Nov 2016 V AGAH QM Workshop November No. 1 15