Framework of Regulation /Guidelines

Transcription

1 Sponsor Responsibility Site Selection Peculiarities of Early Phase Clinical Trials AGAH Workshop, November 03-04, 2016, Bonn Framework of Regulation /Guidelines New Clinical Trial Regulation 536/2014 EU Clinical Trial Dir 2001/20/EC; GCP Dir 2005/28/EC ICH E 6 (R1), Guideline for Good Clinical Practice Integrated addendum to ICH E6 (R1) Eudralex- Volume 10 ICH E 8, General Considerations for Clinical Trials Guideline on strategies to identify and mitigate risks for First-in- Human Clinical Trials with Investigational Medicinal Products EMEA/CHMP/SWP/28367/07 (see also, concept paper on the revision of the said Guideline, EMA/CHMP/446302/2016) Safety pharmacology studies for human pharmaceuticals, ICH S7A AGAH QM Workshop November No. 7 1

2 Framework of Regulation /Guidelines Annex V to procedure for conducting GCP Inspections, Phase I Units EMEA/INS/GCP/197215/2005 Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 ABPI: Guidelines for Phase I Clinical Trials, 2012 Edition MHRA Phase I Accreditation Scheme, version 3, 2015 Guideline on Bioanalytical Method Validation EMEA/CHMP/EWP/192217/2009 rev 1 Early Phase Clinical Trials Nontherapeutic ICH E8 AGAH QM Workshop November No. 7 2

3 Early Phase Clinical Trials A phase I trial: non-therapeutic, exploratory trial. Subjects can usually not expect therapeutic benefit. Complexity of Phase I trials is different for: First in Human Clinical Trials Healthy volunteers <-> patients Single, multi site Single and Multiple Ascending Dose Bioequivalence Trials General Requirement ICH-GCP, E6 AGAH QM Workshop November No. 7 3

4 Investigator s Qualification and Agreements The investigator should be qualified by education, training and experience be familiar with the use of the IP as described in the protocol and the IB be aware of and comply with GCP permit monitoring, auditing and inspections maintain a list of qualified persons to whom he delegates duties. General Requirement AGAH QM Workshop November No. 7 4

5 What makes Early Phase Clinical Trials different regarding site selection? Normally investigational sites are selected by the Sponsor s clinical personnel who will check suitability of a site for the respective trial. Sites capabilities to meet the specific demands for Medical governance Recruitment numbers to be reached Experience of site in the respective indication Experience with dose escalation procedures What makes Early Phase Clinical Trials different regarding site selection? Investigational site Pharmacy CRO / CSC Bioanalytics Dedicated Phase I Units Commercial setting Academic setting Non-dedicated Facilities (multi-site trials) Qualification Audits AGAH QM Workshop November No. 7 5

6 Special Aspects - System QA System in place Independent QA Group Accreditation needed? (obligatory eg in France, Bulgaria..) (CAVE: an accreditation does not negate the necessity for the sponsor s site evaluation) Vendor qualification, if tasks outsourced, and in line with the agreements with sponsor Procedures for Risk Assessment in place? In case of non-dedicated facility (multi-site studies), assess, whether all areas and procedures of the protocol can be controlled Special Aspects - Personnel Investigators need to have a special experience in conducting early phase clinical trials Need to understand pharmacological and preclinical data Also medical staff with appropriate training Especially important for academic units where there might be no dedicated PI for all the trials. Minimum staff levels at dosing days and overnight Intensive life support training AGAH QM Workshop November No. 7 6

7 Special Aspects - Facility/Unit Access controlled, ensured that subjects cannot leave the unit Toilet for drug screening Toilets/ shower to be locked but to be opened from outside by the personnel Equipment qualified and calibrated Leisure area Facilities for meals Special Aspects - Emergency Emergencies evolving from the IMP covered Immediate access to equipment and staff for resuscitating and stabilizing individuals Readily available ICU Rescue medication, antidotes etc. Emergency trolleys, procedure for regular check, check to be documented Emergency training of personnel? Maybe drills Procedure how the emergency staff gets information about the IMP Alarms in all areas which are occupied by subjects AGAH QM Workshop November No. 7 7

8 Subject Recruitment Recruitment strategies From a database Advertisement By worth of mouth By referrals Sites to avoid excessive use of any subject/over volunteering (TOPS in UK) Procedure to identify non reliable subjects Vulnerable subjects, employees of institution At least 3 month waiting period for systemic applications Collect subjects medical history, contact GP Subjects must provide identity TOPS: The Over-volunteering Prevention Scheme 15 Informed Consent Process Often done in a group information session Sites should have a process in place : Who is informing? How can individual questions be addressed? Enough time for consenting? AGAH QM Workshop November No. 7 8

9 IMP Handling and Storage Storage of final IMP at site Accountability Pharmacy involved in: IMP to be prepared further for administration? Labelling? Release? Blinding/randomization? Annex 13 requirements Manufacturing License CAVE: Dose Escalation, randomization procedures Biological Samples Timetables, also indicating allowed ranges Enough staff Laboratories equipped with qualified freezers/refrigerators Labelling procedures in place Sample Blinding procedures in place Robust transport procedures AGAH QM Workshop November No. 7 9

10 Data Recording Subject Medical Record Demographics Medical History, Lifestyle habits Lab print outs Sample preparation and processing sheets..etc. Worksheets Diary (e)crf CSV EDC, barcode system, electronic medical records Source Data Often workbook used, direct entry into the CRF Define source data EDC systems used with barcodes etc. EDC systems to be validated and to comply with e-record, e- signature and data integrity requirements If IT Systems used: physical control, back-up procedures Business Continuity Plan in place Data Protection Rules AGAH QM Workshop November No. 7 10

11 Specifics for BE trials Standardization of diet, fluid intake, Standardization of exercise Administration of Drug: Procedures to identify at any time which product was given to the subjects in which trial phase Check of proper administration: mouth check, QC while administering to avoid subject non-compliance Bioanalytic according to GLP Questions Sigi Duerr, Quality Consultant, AGAH QM Workshop November No. 7 11