Field trial with veterinary vaccine

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2 Field trial with veterinary vaccine Saeedeh Forghani,, M.D. Clinical Trial and Ethics Department Human Health Management Deputy of Quality Assurance 89/4/2 ٢

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4 Introduction: The efficacy and safety shall be demonstrated by experiments under laboratory conditions. The results from laboratory trial shall be supplemented with data from field trial. When efficacy cannot be demonstrated by laboratory trial, field efficacy trials alone may be accepted. ۴

5 Two main reasons: The verification that the results of the efficacy and safety trials, under field conditions and on a large scale. The investigation of efficacy items that cannot be studied sufficiently well under laboratory conditions in the target animals. ۵

6 definition field trial: : a scientific investigation of a veterinary vaccine under field conditions and in target animals,using the product as recommended. Clinical trial: : a systemic study in the species / or in particular categories of the species, for which a procedure is intended ( the target species) in order to establish the procedure's prophylactic or therapeutic effects. ۶

7 Continue a clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health related interventions to evaluate the effects on health outcomes. Clinical trials may also be referred to as interventional trials. Interventions include but are not restricted to drugs, cells and other biological products, surgical procedures, radiologic procedures, devices, behavioral treatments, process of of care changes, preventive care, etc. This definition includes Phase I to Phase IV trials. ٧

8 definition Good clinical practice (GCP)) : A standard standard for the design, conduct, monitoring, recording, auditing, analysis, and reporting of clinical studies. Adherence to the 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 study personnel involved in the study are ensured, and that the environment and the human and animal food chains are protected. ICH: the steering committee of the international conference on harmonization ٨

9 Definition: Field safety trial: to verify the safety to verify the safety of the vaccine under field conditions after one administration of one dose of vaccine as well as after repeated administration depending on recommendation Vaccine efficacy: : to evaluate either on basis of clinical ( protection) ) endpoints and/or validated serological surrogate endpoints whenever appropriate. Efficacy of vaccination is usually defined as the reduction in the chance or odds of developing clinical disease after vaccination relative to the chance or odds when unvaccinated. ٩

10 Implementation of field trial: Field efficacy trial Field safety trial Animal welfare consideration Major uses (critical route, method and regimen of vaccination to be recommended in the most relevant category of target species) ١٠

11 Field efficacy trial: One dose of vaccine used shall not contain significantly more than the minimum titer of the vaccine agent or batch potency to be stated on the label, for live vaccines, the vaccine agent shall be at the highest attenuated passage level that will be present in a batch of the vaccine Challenge of vaccinated animal by exposure to natural infection ١١

12 PRODUCTIVITY 1 parameters Two types of parameters : Main parameters ( mortality, morbidity, lesions, weight gain ) Indicators ( serological response ) qualitative and quantitative correlation between the indicator measured and protection in the target species ١٢

13 2 Control and trial design Vaccinated animals with an equivalent group of unvaccinated or placebo control The controls and vaccinated animals shall be as contemporaneous as possible, preferably investigated at the same time The animals of both groups have to be randomized according to the experimental unit ١٣

14 Continue.. The environment in which the two groups of animals are housed shall be as equivalent as possible or at least as similar as possible The challenge shall be as similar as possible in the two groups of animals. This will not be the case if cohorts consist of exclusively vaccinated animals or controls. ١۴

15 Continue. Combined vaccine : the control group may compromised animals vaccinated with a product formulated to contain all the components of the vaccine except the component under study Double blind placebo controlled Enzootic disease inclusion of controls may be difficult however sufficient evidence shall be presented ١۵

16 3 exposure to infection: The level and moment of exposure shall be the same in both groups of animals. Observation of signs of disease is rarely sufficient and laboratory tests are needed. The agent itself shall be detected and identified. In live vaccine, isolated field strains shall be differentiated from the vaccine strains. ١۶

17 pre existing existing antibody May be : maternally derived (the trial protocol shall include animals with titers of these antibodies normally occurring in the field. due to infection ( immunological status of the vaccinated animals and controls at the time of vaccination is known and a justification for their use is give due to vaccination ١٧

18 Field safety trial : One dose of vaccine shall not contain significantly less than the maximum titer of the vaccine agent or batch potency to be stated on label. For live vaccine, the vaccine agent shall be at the lowest attenuated passage level that will be present in a batch of the vaccine. ١٨

19 Continue.. 1 parameters of safety Local reaction : the size, duration and nature of any lesions at the site of injection Systemic reaction : e.g. mortality, changes in behavior, feed conversation, Side effects effects 2 control and trial design ١٩

20 Animal welfare consideration The use of controls holds the promise of preventing or reducing the future incidence of the disease through the release of efficacious vaccines. Special care should therefore be taken with the study plan in order to respect animal welfare when carrying out such studies. ٢٠

21 Analysis and Interpretation The analysis of the data of field efficacy trials shall be related to the indication and specific claims made for the vaccine and the parameters measured. The analysis of the data of field safety trials shall be related to the recommendation for the administration of the vaccine. ٢١

22 Study Context: Type of Clinical Trial : 1 Confirmatory trial 2 Exploratory trial 3 Composite trial ٢٢

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24 Confirmatory trial Can concern dose determination trials, dose confirmation trials Are controlled Test a hypothesis that is stated in advance Are necessary to provide firm evidence of efficacy and/or in use safety Explain the generalization from the chosen study animal population to the intended target animal population Produce robust results ٢۴

25 Exploratory trial Are precursors to confirmatory trial Have clear objectives May not always lead to simple tests of predefined hypotheses. Contribute to the total body relevant evidence, but cannot be the sole basis of formal proof of efficacy or in use safety ٢۵

26 Composite trial Any individual trial may have both confirmatory and exploratory aspects In confirmatory trials the opportunity may exist to subject the data to further exploratory analyses, which may serve to explain the trial findings and to suggest further hypotheses for research. The protocol should make a clear distinction between those aspect of the trial ٢۶

27 Study scope 1 population 2 primary and secondary variable ٢٧

28 1 population: The choice of subjects maximize the chance of observing specific clinical effects of interest, they may come from a very narrow sub group of the total animal patient population Mirror the intended population To relax the inclusion and exclusion criteria as much as possible with in target indication Cannot be expected to be totally representative of the future target population ٢٨

29 2 Primary and Secondary variables Primary variable: The primary variable known as the primary endpoint variable Related to the primary objective of the trial Generally there should only be one Primary variable Derived from experience in previous studies or in published scientific literature secondary variable Either supportive measurement related to the primary objective or measurement of effects related to the secondary objectives ٢٩

30 Design technique to avoid bias 1 Blinding 2 Randomisation ٣٠

31 Blinding To limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial which may arise from the knowledge of specific treatment a study animal may be receiving or is about to receive. Full blinded trial Partially blinded trial Open label trial ٣١

32 Randomization Introduces a deliberate element of chance into the assignment of treatments to subjects in a clinical trial. Documents the random allocation of treatments to study animals. In the simplest form it could be a sequential list of treatments or corresponding codes by subject number. Different study designs will require different procedures for generating randomization schedules. ٣٢

33 1 Study Configuration: a Parallel group design: The most common clinical trial for confirmatory trial Study animals are randomized to one of two or more arms, each arms being allocated a different treatment b Cross over design: Each study animal is randomized to a sequence of two or more treatments, and hence acts as its own control for treatment comparisons. Reduces the number of animals ٣٣

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35 Continue... c Factorial designs: Two or more treatments are evaluated simultaneously in the same set of subjects through the use of varying combination of the treatments. In many cases this design is used for the specific purpose of examining the interaction of A and B. To establish the dose response characteristics of a combination product ٣۵

36 2 Multicenter trials: Only laboratory studies or exploratory field studies can be carried out at a single site. Two Maine reasons: firstly, it is an accepted way of evaluating a new medication more efficiently secondary, to provide a better basis for subsequent generalization of its findings. ٣۶

37 3 Type of comparison 1 Trial to show Superiority: efficacy is most convincingly established by demonstrating superiority to placebo in a placebo controlled controlled trial, by showing superiority to an active control treatment or by demonstrating a dose response relationship. 2 Trial to show Equivalence or Non inferiority: is divided into two major categories according to its objectives, one is an equivalence" trial and the other is a non inferiority trial. ٣٧

38 Continue. 3 Dose response Design: May serve a number of objectives: The confirmation of efficacy The investigation of the shape and location of the dose response curve The estimation of an appropriate starting dose The identification of optimal strategies for individual dose adjustments The determination of a maximal dose ٣٨

39 Continue. 4 Group Sequential Designs To facilitated the conduct of interim analysis ٣٩

40 5 Experimental unit In veterinary clinical studies there are variety of situation where the experimental unit is not the animal but a pen, room, pasture or litter, as well as an udder quarter for milking cows. The experimental unit should be clearly specified in the protocol, since it is essential to the sample size calculation. ۴٠

41 5 Sample size Determined by the primary objective of the trial The method by which the sample size is calculated should be given in the protocol In confirmatory studies, assumption should normally be based on published data or on the results of earlier studies. Sample size calculation should refer to the number of experimental units required for the primary analysis. ۴١

42 6 Data capture and analysis ۴٢

43 References Note for Guidance field trials with veterinary vaccines (EMEA) Practical advice on designing and conducting effective veterinary clinical trial (PTI) Good clinical practice for the conduct of clinical trials on veterinary erinary medicinal products in the European Union ICH Harmonized tripartite guidance (statistics in medicine) International Clinical Trials Registry Platform (ICTRP who) ۴٣