Field trials/ Clinical trials

Dr. Bhoj R singh, Principal Scientist (VM)I/C Epidemiology; Centre for Animal Disease Research and Diagnosis

Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, UP, India. TeleFax  +91-581-2302188

Types on the basis of purpose

• Pharmacological and toxicity trials: Either in Lab animals or Target spp.

• Initial trials for therapeutic effect and safety: In target spp. under controlled environment specifically to select the most effective agent out of the several potential ones, standardized the therapeutic/ prophylactic dose/ schedule

• Clinical evaluation of efficacy: On large scale, in field, under operational conditions usually multi-centric to evaluate the effect of several factors including environment.

• Post authorization surveillance: To monitor adverse effects/ reactions.

Field trial Clinical trialIn healthy population On patients

Often prophylactic Often therapeutic (including prevention of sequelae)

Relies on natural challenge

No Challenge

For primary prevention

For secondary and tertiary prevention

Types of trials on the basis of control• Uncontrolled/ Open: The same group /

individual is compared before and after treatment/ vaccination.

• Controlled trials: Treatment and Control groups are always there.– Concurrent Control– Historical control– Positive control– Negative control– Randomized control (Approach is similar as used for

cohort studies)

On the basis of scale• Exploratory trials: For proof of efficacy, less stringent.• Confirmatory trials: Randomized controlled trials to

determine appropriate dose level, with stringent protocol. • Composite trials: Combines both exploratory and

confirmatory trials.• Community trials: Experimental unit is entire

community, population of a defined area/ breed, sex, species etc.

• Multi-centric trials: May be for any purpose but mostly for confirmatory objective with aim to recruit more animals in the trial, to increase validity through having a large cross section of population as study population.

More types

• Superiority trials: To determine difference between treated and control group, based on outcome.

• Equivalence or Bioequivalence trials: To compare the treatments with almost same or similar outcome for economy of the therapeutic agent, availability, simplicity in use, acceptability etc.

• Non-inferiority trails: To prove that new drug is as good as the standard one.

Considerations before Trial protocolPrimary hypothesis: Feeding GN cake increases fat in milk. It is

identified by measuring the effect/ response variable e.g. milk fat in milk of two groups, the fat % in milk is the Primary end point (the end point which is clinically/ economically most important, can be measured easily and economically) and Secondary end points (type of fats/ fatty acids etc.). It should define the validity of the hypothesis. In exploratory trials it is often desirable to use more than one primary end point to cover the potential range of effect as in this case concentration of milk protein, milk fat, mineral contents, SNF, metabolic disorders, post-partem breeding etc.

Determining the efficacy: For calculation mean values are taken either as mean of all experimental units separately or in group, to determine Treatment efficacy (λexp) λexp= Fat % in GNC fed (T) – Fat % in control (C) / Fat% in Control (C) % efficacy=(C-T)*100/C

• Experimental unit: Usually an individual animal, but in livestock allocation of treatment groups (as in feeding trials when it is not easy to determine how much feed an individual consumed, then animals in a household/ birds in a pen may be taken as unit) . Sometimes there may be several units within an animal as different quarters of udder may be separate units (for intramammary infusion of treatment), two horns (horn cancer treatment), different legs (for effectiveness of a lotion to be applied in foot rot, FMD lesions etc.).

• Experimental population (EP): The population on which a trail is conducted, it should be true representative of a Target population. If there is difference in two populations then external validity of the findings will be low. When there is biasness in allocation to groups (T and C) in EP then the internal validity is low. Prophylactic trials often target the populations with high risk of exposure or probability of development of a natural disease so that natural challenge can have play.

• Admission/ eligibility and Exclusion criteria: For inclusion/ admission protocol must precisely define the condition and criteria for diagnosis of the condition. For exclusion, protocol must define the criteria of not including a case in the study (as allergic to treatment, having some other condition/ disease, previous treatment etc).

• Blinding: Single, double, treble and open label (non blinded).

Trial protocol

• General information (title, Name and add. of Investigator, sponsor, trial sites etc.)

• Justification and objectives (Need, reasons, primary hypothesis, primary end point, secondary hypothesis to be tested).

• Design (Effect/ response variables, scoring system, affectivity definition etc.)• Duration (Date of beginning, ending, duration of the target disease, period of

recruitment, duration of treatment, observation, rules for termination of trial).• Experimental population (Unit, composition, inclusion/ exclusion criteria,

definition of cases, diagnostic criteria, selection of control, sample size, informed consent).

• Therapeutic/ prophylactic procedure (Product formulation and identification, dosages, placebo/ standard treatment formulation and identification, route and frequency of administration, operators’ safety, environmental safety, blinding method, compliance monitoring, definition of stage to stop intervention).

• Type of trial (randomization, stratification, implementation of allocation process).

• Data collection (dates, frequency, method of recording adverse reactions, identification of experimental units, training/ standardization of data collection and recording, confidentiality, communication with and between participants).

• Data analysis (Technique of unblinding, statistical method, significance level and confidence interval for interpretation, method to ‘lost to follow up etc.)

Trial designs

• Parallel-group (Standard): Mostly in confirmatory trials, experimental units (EU) are randomized for single treatment.

• Crossover design: EUs are exposed to more than one treatment consecutively for each treatment EUs are allocated through randomization. Applicable where treatment effect do not carry-over in to subsequent treatment period.

• Sequential design: Conduction is dependent on the results obtained so far and EUs enter the trial in pairs (T and C) and observed for desired level of effect to enter in to second stage or terminate the trial or to to increase the sample size (open trial). Significance tests are conducted repeatedly on accumulating data, it tends to increase significance over the time.

• Factorial design: If two treatments, A and B needs to be investigated at two levels (a and b) then the factorial designs are made and in this case we designate it as a×b factorial design. It is powerful but a bit complicated design in 2x2 factorial design there are 4 treatnments viz., A, B, A&B, Neither A nor B.