Medicines inspections technical updates: Contract research organizations (CROs)

Transcription

1 JOINT UNICEF, UNFPA & WHO MEETING WITH MANUFACTURERS AND SUPPLIERS OF CONTRACEPTIVE DEVICES, IN VITRO DIAGNOSTICS PRODUCTS, VACCINES, FINISHED PHARMACEUTICAL PRODUCTS, ACTIVE PHARMACEUTICAL INGREDIENTS AND VECTOR CONTROL PRODUCTS Medicines inspections technical updates: Contract research organizations (CROs) Vimal Sachdeva, Technical Officer (Inspector) WHO Prequalification Team (PQT), WHO/HIS/EMP/RHT 20 Avenue Appia, CH , Geneva 27, Switzerland Tel.: Fax: sachdevav@who.int 1

2 TALKING POINTS International Norms, standards & guidelines Essentials of bioequivalence (BE) study Key components BE study Inspection of clinical and bioanalytical parts Analysis of Inspection Findings Consideration Concluding Remarks 2

3 PREQUALIFICATION PROGRAMME: INTERNATIONAL NORMS, STANDARDS AND GUIDELINES USED IN INSPECTION ACTIVITIES Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. World Health Organization, 1995 (WHO Technical Report Series, No. 850), Annex 3. Annex3.pdf Guidance for organizations performing in vivo bioequivalence studies. WHO Technical Report Series, No. 996, 2015, Annex 9 HANDBOOK FOR GOOD CLINICAL RESEARCH PRACTICE (GCP) Guidance for implementation EMA guideline on bioanalytical method validation FDA guidance for industry: Bioanalytical Method Validation Guidelines for the preparation of a contract research organization master file. World Health Organization, WHO Technical Report Series, No. 957, 2010 Annex 7, Page

4 ESSENTIALS OF BE Design, conduct and evaluation of bioequivalence studies Pharmaceutical equivalence Method: in principle comparative pharmacokinetics (AUC, C max ) Acceptance criteria: comparative rate and extent of absorption The formulation and the characteristics of the active substance are factors which can affect the requirements for bioequivalence studies. 4

5 ESSENTIALS OF BE Bioequivalence studies: in vivo comparison of products by means of volunteers serving as in-vivo dissolution model biological quality control comparison of product characteristics to ensure therapeutic equivalence 5

6 Demonstration of bioequivalence Bioequivalence study on healthy volunteers or ONLY EXCEPTIONAL! PD studies Clinical studies In vitro methods 6

7 WHAT ARE THE KEY COMPONENTS OF A BIOEQUIVALENCE STUDY INSPECTION? Clinical Part: Consists of verifying how the study was actually conducted on trial subjects Bioanalytical Part: Consists of verifying how the subject's samples were handled, processed, tested and how plasma/ blood drug concentrations were calculated for each subject Other: Statistics, quality assurance, communications between departments, archiving, etc. 7

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9 INSPECTION OF CLINICAL PART OF BE STUDIES-1 Premises Flow Registration, screening, change room, examination, physical, ECG, dining room, recreation, dosing, sampling, centrifuge, ward, nurses room, custodian, toilets, pharmacy, freezers Volunteers: Bank Number allocation ID card, record of participation DOB verification, address etc Previous study participation record Number in study - rationale List of signatures for payment Staff: List of signatures - staff Number of phlebotomists and stations, subjects ratio Training of staff for the protocol - minutes Investigator and others: CVs Protocol: Version, amendments and deviations Contents Declaration of Helsinki Randomization: programme, print out, date 9

10 INSPECTION OF CLINICAL PART OF BE STUDIES-2 Ethics Committee: Notice of meeting, agenda Minutes Protocol and ICF Where meet, secretary, who present Payment General screening and IC - approval Screening (general?) - validity ICF: Signed, dated Insurance Language Source data: Inclusion / Exclusion criteria Age, height etc Dosing sheets vs randomization Labels Bleed sheets and times, ID checked Phlebotomists Vitals PI and PII ADE Concomitant medication Sample transfer; Sample to freezer; Sample to centrifuge Total number of samples, reconciliation Menu; meals taken 10

11 INSPECTION OF CLINICAL PART OF BE STUDIES-3 Pharmacy: Shipping letter Receiving letter COA Reconciliation Dispensing SOP and record Registers (access, activity, cupboard, archive) Temp and RH SOPs all activities Monitor: Appointed Before, during, after Reports Responsibilities QA Audits: Before, during, after Reports 11

12 INSPECTION OF CLINICAL PART OF BE STUDIES-4 DOCUMENTATION REVIEW MAY INCLUDE: Master lists for subjects Investigational medicinal products, COAs, accountability and dispensing records; Laboratory results/data, ECGs and X ray films; Logs, registers and records Training SOP and records Lists of staff present during each study Screening records (incl general screening forms and data) Check in records Final list of volunteers enrolled Master list of signatures of volunteers Personal belongings, Catheter in and out Payment verification Meals and records, correspondence with dietician and caterer Custodian reports Check out data Sample transfer records Adverse Drug Event reporting Concomitant medication Informed Consent Forms Justification for the number of volunteers for the study Demographics versus report versus dossier Product dispensing Product administration Blood sample collection Case Report Forms 12

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14 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY ELEMENTS OF INSPECTION Personnel: Organization, responsibilities CVs signed and dated Laboratory inspection: (E.g. Premises, equipment, personnel, documentation) Equipment / Instruments Balances ID, maintenance logs, calibration log, daily check Pipettes ID, recorded and calibrated. Sample logbook Transfer of samples from clinical Record for receiving samples (date, qty, temp etc) Deep Freezers and fridges ID Samples In and out logbooks / registers Data logger print out (records T) Qualification, Calibration, Mapping HPLC / LC MSMS Columns SOPs, records, logs, maintenance Qualification etc. Reference standards: COA of reference substance - WS from Sponsor 14

15 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Elements of inspection Documentation review: Samples inward record Allocation of staff for activities Training of staff prior to the study Analytical methodology Solution preparation and batch allocation History of study activities Repeat analysis record System suitability Screening of biological matrix Receiving, storage and retrieval of CC and QC samples Retrieval of study samples Sample dilutions Documentation review (2) Maintenance logs for equipment Use logs for equipment and parts (e.g. columns) Reference standards: preparation, storage, use Procedure for method validation and method validation data including specificity, serial dilutions, precision, accuracy, ruggedness, and recovery Sample stability source data and report including sort term, long term, bench top, freeze-thaw, in-injector stability, long term of analyte in matrix Manual calculations for the concentrations Chromatograms for subjects for different periods SOPs and records in the lab Qualification protocols and reports 15

16 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Validation of an analytical method-1 Method validation should be performed for any analytical method whether new or based upon literature. to demonstrate the reliability of a particular method for the determination of an analyte concentration in a specific biological matrix, such as blood, plasma, urine, saliva or tissue. Should be performed using the same anticoagulant as for the study samples. 16

17 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Validation of an analytical method-2 Reference standards During method validation, a blank biological matrix will be spiked with the analyte of interest using solutions of reference standard. In addition, an internal standard (IS) is normally used in chromatographic methods. Quality control (QC) sample A spiked sample used to monitor the performance of a bioanalytical method and to assess the integrity and validity of the results of the unknown samples analyzed in an individual batch. 17

18 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Validation of an analytical method-3 The quality (purity) of the reference standard and IS may affect the outcome of the analysis, and therefore the outcome of the study data. should be obtained from an authentic and traceable source. compendial standards (EPCRS, USP, WHO), commercial available standards, fully characterized standards prepared in-house or by an external non-commercial organization Suitability of the reference standard should be scientifically justified. When MS detection is used in the bioanalytical method, a stable isotope-labelled IS is recommended to be used whenever possible. 18

19 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Validation of an analytical method-4 Validation involves documenting, performance characteristics of the method that are suitable and reliable for the intended analytical applications. accuracy, precision, selectivity, sensitivity, reproducibility, Carryover, Lower Limit of Quantitation Calibration Curve (CC) Dilution integrity Matrix effect Stability covering freeze thaw, long term stability of analyte in matrix 19

20 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Validation of an analytical method-5 Partial validation Where minor changes are made to a validated analytical method. Such changes include: transfer of the bioanalytical method to another laboratory, change in equipment, calibration concentration range, storage conditions etc. the scope of revalidation or partial validation should be justified. In most cases, provision of additional accuracy and precision data or relevant additional stability data on the modified issue may be sufficient. Cross validation Where data are obtained from different study sites, a cross validation of the applied analytical methods should be carried out. e.g. differences in sample preparation or the use of another analytical method. Should be performed in advance of study samples being analysed. the same set of QC samples should be analysed by both analytical methods. The difference between the two measurements should not exceed 15%. 20

21 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Analysis of study samples-1 Depending on the time period between validation and the analysis of the study samples it may be necessary to verify the performance of the method before start of the analysis of study samples. The study samples should be processed in accordance with the validated analytical method, and together with the QC samples and the calibration curve (CC) to ensure the acceptability of the analytical run. 21

22 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Analysis of study samples-2 Analytical run An analytical run consists of: the blank sample (matrix without analyte and without IS) a zero sample (processed matrix with IS) a set of calibration standards at a minimum of 6 concentration levels at least 3 levels of QC samples (low, medium and high) in duplicate) study samples to be analyzed All samples (calibration standards, QC, and study samples) should be processed and extracted as one single batch of samples. Analyzing as a single analytical run samples prepared separately as several batches should be avoided. If such an approach cannot be avoided, for instance due to bench-top stability limitations, each batch of samples should include low, medium and high QC samples. Acceptance criteria should be pre-established in a Standard Operating Procedure (SOP) or in the study plan and should be defined both globally for the full analytical run, and for each individual batch of samples. 22

23 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Analysis of study samples-3 Analyze all samples of one subject together in one analytical run to reduce the variability in outcome. it is acceptable to analyze study samples of more than one subject in one analytical run. The QC samples should be divided over the run i.e. at the beginning, middle and at the end of the run. It is also acceptable to place one of each low, medium and high QC samples at the beginning of the analytical run followed by the study samples and at the end of the run again one of each low, medium and high QC samples. 23

24 INSPECTION OF BIO-ANALYTICAL PART OF BE STUDY Analysis of study samples-4 Reanalysis of study samples Should be predefined in the study protocol or SOP, before the actual start of the analysis of the samples. The number of samples (+ % of total number of samples) that have been reanalysed should be discussed in the study report. The reanalysed samples should be identified and the initial value, the reason for reanalysis, the values obtained in the reanalyses, the finally accepted value and a justification for the acceptance should be provided. The following reasons can be identified to reanalyse study samples: rejection of an analytical run because the run did not fulfill the acceptance criteria with regard to accuracy and precision of the calibration standards and/or QC samples, internal standard response significantly different from the response for the calibration standard and QC samples, if such criteria have been pre-defined in a SOP, improper sample injection or malfunction of equipment, the obtained concentration is above the ULOQ or below the run s LLOQ, in runs where the lowest standard sample has been rejected from a calibration curve, resulting in a higher LLOQ compared with other run s, identification of sample analyte in pre-dose samples or placebo sample, poor chromatography. Reanalysis of study samples because of a pharmacokinetic reason is not acceptable. This is especially important for bioequivalence studies, as this may affect and bias the outcome of such a study. 24

25 Inspection of Bio-analytical part of BE Study Analysis of study samples-5 Re-injection Re-injection of samples can be made in case of instrument failure if reinjection reproducibility and on-injector stability have been demonstrated during validation. Re-injection of a full analytical run or of individual calibration standard samples or QC samples, simply because the calibration or QCs failed, without any identified analytical cause, is not acceptable. Integration Chromatogram integration should be described in a SOP. Any deviation from this SOP should be discussed in the analytical report. 25

26 ANALYSIS OF INSPECTION FINDINGS 26

27 WHO inspections: Contract research organizations Year Number of inspections Year Year Year Year Year Year up to date

28 Year 2016 CRO Inspections Year 2016 CRO Inspections Routine Initial Total 43% 57% Routine Initial CRO inspections per country Initial Compliance status CROs % India 29% 57% Awaits CAPA Non compliant Jordan Compliant 6 28

29 DURING THE INSPECTION: Recurring deficiencies that have failed studies: 2 main categories of deficiencies have been recurring over the last 10 years: Falsified/ Inadequate/Unreliable/Incomplete documentation Ethical issues 29

30 Sponsor Lack of involvement and responsibility of sponsor No evidence of assessment of the trial site (labs, equipment, staff, facilities) No monitors appointed by the sponsor. No audits performed sometimes audits performed after the report was issued No monitoring / audit reports available. 30

31 Ethics Committee (IEC or IRB) It was not possible to conclude that the IEC was independent in its decision making process. The "Independent Ethics Committee" - only reviews protocols from the CRO - was set up by sponsor. All secretarial activities including the "secretary" provided by the sponsor. The IEC file, which includes the meeting minutes, is maintained by the sponsor. The minutes from the IEC meeting, which included study XYZ, indicated that the clinical investigator was also the member secretary for the IEC. 31

32 Case Report Forms (CRFs) Not specific to the study Errors on the CRFs Laboratory reference ranges on CRF different from those reported by the laboratory Appearance of tablets incorrectly described Missing: Laboratory results (source data), ECGs Final study report not signed by the monitor 32

33 Bio-analytical part Batch numbers of reference substances used were not documented Were the batches used, those for which COAs were available? Not possible to verify purity of reference substances! Only uncertified copies of chromatograms at the CRO (original chromatograms reportedly sent to sponsor) Documents relating to chromatographic analysis of samples not available during the inspection. 33

34 Errors in dilutions of stock solution (e.g.: errors were found in the documentation relating to the preparation of stock solutions and of calibration and control samples. This affects the concentration of all calibration and control samples and therefore of all subject samples). Quantity of QC and calibration samples prepared not consistent with the number of results reported. e.g.: The volume of calibration and control samples prepared is insufficient when compared to the volumes used for calibration samples levels 3, 4, 6 and 8, there was no documented evidence showing the preparation of additional calibration and control samples). After inclusion of all results of QC, accuracy and precision did not meet the acceptance criteria for the method and all accepted runs had not at least 50% of each QC within 15% of its nominal value. E.g.: Exclusion of QC results in the report for other reason than analytical problem, the results of all QC samples for which the result obtained deviated from the nominal concentration by more than 15 % were excluded from statistical calculations). For long term stability of samples, QC and calibration samples used as reference were not freshly prepared. No long term stability data covering the retention time of the samples for the second analysis) Laboratory notebook did not enable all operation realized and operator involved to be traced. 34

35 Manual reintegration of peak (baseline, etc.) not done appropriately and consistently for all peak inclusive internal standard For some samples checked, especially QCs or standards close or outside the 15% of their nominal concentration, the baseline of the chromatograms were modified manually. This was not done appropriately and consistently for all peaks inclusive internal standard, For the study itself, several run did not include enough QC, only one QC at each concentration (LQC, MQC, HQC) was processed in one batch For modified integration, initial integration was not available. No paper or electronic audit trail of manual integration available. Each analytical run did not include calibration and quality control samples. 35

36 Integration: risk of data manipulation 36

37 Integration: direct influence on concentration 37

38 Record Modification! 38

39 Analysis of subject samples Typical output from Analyst Nominal Back-calculated % of nominal 39

40 Analysis of subject samples Unticked: not used for calculations % > 115 % 40

41 CONSIDERATIONS Understand your product and characterize properly biobatch (drug development) Understand your manufacturing process Understand your reference product Decide about possibility of bio-waiver Select and purchase comparator in line with requirements Select qualified CRO Ask WHO-PQP for advice on study protocol Monitor/audit CRO (GCP, bioanalytical methods). 41

42 SUMMARY CRO/BE Inspections are an important part of the WHO-PQP evaluation process International norms, standards and guidelines are used in inspection activities to ensure wide applicability Not all studies are inspected: Risk management principles are applied to ensure efficient use of available resources Inspection results show that there are still a lot of poor clinical and bioanalytical practices out there. In particular, data integrity and Good Data Management Practices need to be improved in the industry overall Results show that WHO-PQP has made tremendous contribution in this respect. 42

43 Thank you for your attention! 43