VICH GL 9 Good Clinical Practice David Murphy

VICH GL 9: Good Clinical Practice David Murphy, HPRA, Ireland Gesine Hahn, BVL, Germany VICH Veterinary Outreach Forum, Tokyo, 19 -20 November, 2019

Disclaimer In the view of the presenter, these slides are consistent with relevant VICH guidelines and have been provided for training purposes only. As always, the original Guideline should be used as the primary source of information for working with regulators. 2

This presentation will cover > What is GCP? > History of VICH GL 9 > Benefits of VICH GL 9 > Key elements of GCP • • • Roles and responsibilities Study protocol Final study report Data handling and documentation Quality audits > Approach to assessment > Conclusions 3

What is GCP? 4

What is GCP? • Scientific and ethical quality standard for designing, conducting, monitoring, recording, auditing, analysing and reporting clinical studies evaluating veterinary medicinal products in the target anial species • To be followed when developing clinical study data that are intended to be submitted to regulatory authorities. 5

What is GCP? Clinical studies: A single scientific experiment conducted in a target species to test at least one hypothesis relevant to the proposed effectiveness claim(s) or to inuse safety in the target animal for a veterinary product under investigation. (VICH Gl 9, glossary) The purpose of a clinical study may be confirmatory (e. g. , typical field study), exploratory (e. g. , dose finding, TAS) or composite, i. e. further exploratory analyses to explain the study results and to suggest further hypotheses for research 6

What is GCP? Adherence to the GCP standard provides assurance that the data and reported results are complete, correct and accurate, that the welfare of the study animals and the safety of the personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected. 7

History of VICH GL 9 8

How and when did it start The VICH Process Start of the work in 1997 EWG consensus in Sept. 1998 (step 2) SC approval of release for consultation in Oct. 1998 (step 4) EWG consensus in Nov. 1999 (step 5) SC approval in Feb. 2000 (step 7) Implemention date of July 2001 9

Benefits of VICH GL 9 10

The benefits of GCP • Internationally recognised scientific standard format • Ensures integrity of the clinical study data and transparancy of the procedures • Compliance gives regulators and the general public confidence in the results • Facilitates mutual acceptance of clinical study data by the competent authorities • Unnecessary repetition of trials is avoided 11

Key elements of GCP 12

Key elements of GCP Concept of quality assurance (QA) • Clearly defined roles and responsibilities of the personnel involved • Clearly defined procedures (study protocol and SOPs) • Defined requirements on reporting (Final Trial Report), data handling and retention • Quality audits 13

Key elements of GCP The Sponsor • Provides sufficient scientifically valid information upon the effectiveness and safety of the IVMP • Notifies/applies the conduct of the study to regulatory authorities • Selects the investigator(s) • Appoints the monitor(s) • Prepares a study protocol in consultation with the investigator • Maintains the study documentation 14

Key elements of GCP The Investigator • Qualified by scientific training and expertise • Responsible for all aspects of the study • Promptly notifies the sponsor of any study protocol deviation, AEs • Permits monitoring, QA auditing 15

Key elements of GCP The Monitor • Link between investigator and sponsor • Trained in quality control techniques • Visits and contacts the investigator before, during and after the study • Reports any adverse event to the Sponsor 16

Key elements of GCP The Study Protocol (1) • Clear and precise description of the objective of the study • Clear description of the study design (control methods, method of randomization, blinding techniques) • Precise description of the study population üAppropriate inclusion/ exclusion criteria üConcomitant treatments (permitted, not permitted) üAnimal husbandry and feeding management • Treatments, clear identification of the IVMP and control product 17

Key elements of GCP The Study Protocol (2) • Efficacy assessment üAppropriate primary/ secondary endpoints üClinical observations and other special tests or analyses üTiming and frequency üPost-observation period üScoring systems and measurements need to be clearly defined üMethods of computing and calculating effects • Monitoring of adverse events üTiming and frequency of observations üAny corrective action 18

Key elements of GCP The Study Protocol (3) • Statistics üClear description of the statistical methods including hypothesis to be tested, the parameters to be estimated, the assumptions to be made and the level of significance, the experimental unit and the statistical models üThe planned sample size should be justified. üHandling of missing data and outliers Note: The purpose of the study should be to get a statistically significant and clinically relevant answer 19

Key elements of GCP The Study Protocol (4) • Established before study initiation and signed/dated by the sponsor and investigator • Can not be changed unless everyone agrees in writing („amendments“) • Any deviation occuring during the study must be recorded, explained and signed by the investigator 20

Key elements of GCP The Study Protocol (5) Supplements to be appended • Standard operating procedures that are specific to the study • Copies of all data capture and event record forms • Relevant information provided to the owner • Instructions to technical staff 21

Key elements of GCP The Final Study Report • Comprehensive description of the study – objectives, methods, materials including statistical methods • Written by the sponsor and/or investigator • Generally follows the structure of the study protocol • Critical evaluation of the results, descriptive statistics (tables and graphical presentations) • Details of any AEs • Conclusions 22

Key elements of GCP Data handling and documentation • Data recording • Data collection, basic data management procedures • Data retention 23

Key elements of GCP Quality audits • Systematic and independent control of study activities, recommended but not required. • May include audits of the protocol, critical phases of the study, data capture form completion, data listing, summaries and analyses, final study report. 24

Approach to assessment 25

Approach to assessment Fundamental questions to be considered: • Do you have confidence in the conduct and findings of the study? • Do the findings confirm efficacy of the product for the proposed indication when administered at the proposed posology? • Is the product safe for the target animal under conditions of normal use? 26

Approach to assessment GCP compliance – what do we look at? • GCP compliance statement, dated and signed (usually sponsor, investigator, monitor, statistician) • Audit reports or certificates • Final study report • Study protocol + appendices (amendments, deviations, SOPs) • Animal owners informed consent • Any other report, e. g. safety report, statistical report • Animal data listing • Products (test, control) 27

Approach to assessment Study conduct – what do we look at? • • • 28 Is the study objective clear? Is the study appropriately designed for that objective? Is the study controlled? Is the control appropriate? What is the approach to randomisation and blinding? Is the test population representative of the target population? (where, when. . )

Approach to assessment Study conduct – what do we look at? • What is the approach to evaluation of efficacy? Is it appropriate? • Primary endpoint must reflect the intended treatment claim. • If a scoring system is used, is it clearly described/defined such that it can be applied consistently and reliably interpreted? • If using a surrogate parameter, must correlate with clinical effect. • Is the timing and frequency of efficacy observations appropriate? • Were animals excluded from efficacy evaluation? If yes, why? • Was the statistical analysis appropriate? • Is there a treatment effect? Is it clinically relevant? 29

Approach to assessment Study conduct – what do we look at? • What is the approach to evaluation of safety? Is it appropriate? • Parameters evaluated (clinical, haematological, biochemical. . . ). • Timing and frequency of observations, measurements. • Were appropriate actions taken in response to observed adverse effects (appropriate medical treatment)? • Were animals excluded from safety evaluation? If yes, why? • Are there treatment-related adverse effects? 30

Conclusions 31

Conclusions From a regulatory point of view • One of the most important guidelines • Facilitates the review of clinical studies because of the used standard terminology, formats and structure of the study documentation • Allows for transparancy of procedures • Gives assessors confidence in the results • But, will not compensate for poorly designed studies! 32

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