Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and
AWA – Animal Welfare Act – regulates the treatment of animals in research, exhibition, and by dealers; enforced by the USDA, APHIS. https://www.nal.usda.gov/awic/animal-welfare-act
Canine Brief Pain Inventory
Composite Measure Pain Scale
Canine Orthopedic Index
Conditioned Pain Modulation
Degenerative Joint Disease
Diffuse Noxious Inhibitory Control
Functional Data Analysis (and Food and Drug Administration!)
Feline Musculoskeletal Pain Index
Helinski Chronic Pain Index
Liverpool Osteoarthritis in Dogs
Montreal Cat Assessment Tool
Nociceptive threshold testing
Nociceptive Withdrawal Reflexes
Peak Vertical Force
Radiation Associated Pain
formed or conceived beforehand
A device that measures activity. Note: there is no standard measure of activity or ‘activity count’
Recording movement using an activity monitor
Measurement of changes in acceleration. Different methods can be employed ranging from ‘zero crossing’ to an integrated function of the intensity and duration of acceleration change.
An active ingredient is any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.
The initial assessment at the start of a study.
BASIC SCIENTIFIC RESEARCH
This term is usually used to differentiate studies involving patients (clinical research) from preclinical research involving in-vitro work or work involving experimental animals. See also ‘fundamental research’.
Systematic error that misrepresents the association between the treatment and outcome
A characteristic that is objectively measured and evaluated as an indicator or normal biological process, pathologic processes, or biological responses to a therapeutic intervention. A biomarker can be physiologic, pathologic, or anatomic characteristics or measurement that is thought to relate to some aspect of normal or abnormal biologic function or process. Biomarkers measured in patients before treatment can be used to select patients for inclusion in a clinical trial. Changes in biomarkers following treatment may predict or identify safety problems related to a candidate drug, or reveal a pharmacological activity expected to predict an eventual benefit from treatment.
Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources — human, animal, or microorganism — and may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.
Scientific research that relates to, informs or applies to clinical medicine or clinical veterinary medicine.
A blind or blinded (also called ‘masked’) experiment or trial is where information about the test is masked (kept) from the participant +/- those involved in the work to reduce or eliminate bias, until after the outcome (results) is known. Single blind relates to the patient not knowing what intervention they are on. Double blind refers to the patient and the study personnel not knowing. Triple blind study refers to statisticians also being blinded during analyses.
CARE-GIVER PLACEBO EFFECT
Effects that alter the rating of outcomes provide by clinicians, caregivers, or the family. A sham medical intervention that causes pet caregivers (owners or veterinarians) to believe the treatment they provided to the pet improved the pet’s condition
Research based on one or a few patients. Good for generating hypotheses, but not appropriate for testing hypotheses.
CLINICAL OUTCOME ASSESSMENT
COA measures a patient’s symptoms or clinical signs, overall mental status, or the effects of a disease or condition on how that patient functions. COAs can be used to determine whether or not a drug has been demonstrated to provide treatment benefit. A COA is composed of a measure that produces a score together with clearly defined methods and instructions for administering the COA and assessing response; a standard format for data collection; and well-documented methods for scoring, analysis, and interpretation of results in the targeted patient population. COAs can provide direct or indirect evidence of treatment benefit. For COAs that provide indirect evidence of treatment benefit, qualification also includes a review of the evidence that the COA is adequately related to how patients feel or function in daily life.
Studies involving patients (human or owned animals) or material (biological samples or outcome data) collected from patients.
Studies involving patients (humans or owned animals) and an intervention that is being tested (trialed).
CLINICAL METROLOGY INSTRUMENT (CMI)
A clinical metrology instrument (CMI) is a sequence of items which are ascribed a score based on the subjective experiences or observations of the person completing it. These scores are then usually processed in some way to quantify the level of disease.
A research method concerned with observing events involving a particular group of patients over time.
An instrument that measures the combined aspects of the disease/condition into a single numerical value.
Evidence that relationships among items, domains, and concepts conform to a priori hypotheses concerning logical relationships that should exist with other measures or characteristics of patients and patient groups. Testing that is used when the tool is measuring something (a construct) that cannot be directly observed (pain, quality of life etc.). While the construct can not be directly seen, behaviors resulting from it can be observed. Obviously, it will be impossible to ‘prove’ that something that cannot be measured directly is being measured. Several approaches can be used:
• Hypothesized factors tested with factor analysis
• Discriminatory validity: Does the instrument discriminate between subjects with and without the condition? Does it discriminate between different severities of the condition?
• Responsiveness of the tool to a treatment known to change what is being measured, or to a change in the condition over time
• Correlation to overall quality of life
Evidence from qualitative research demonstrating that the instrument measures the concept of interest including evidence that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use. Testing other measurement properties will not replace or rectify problems with content validity.
In the context of clinical trials, a group of subjects that are not treated with a defined intervention in a study, and used to compare the effects of an intervention or treatment. Control groups may have the condition of interest, and can be POSITIVE (given an active comparator intervention) or NEGATIVE (receive no intervention). Control groups can also be UNTREATED CONTROLS.
In the context of clinical trials , a study in which non-treated subjects are included to determine if the effects measured are due to the intervention or not. To minimise bias such studies are often randomized (there is an equal chance of any individual being allocated to either the active or the control group) and (double or single blind) placebo controlled.
Refers to the extent to which the measure agrees with the external standard measure. For example, the extent to which the scores of a subjective instrument correlate with some other measure – a measure accepted as the ‘gold standard’. Often, in the development of subjective assessment tools, the best approach is to use an accepted objective measure. Because pain cannot (yet) be directly measured, an objective surrogate measure can be used, e.g. an objective measure of activity if pain is expected to impact activity.
A cross-sectional study is an observational study, in which the observations (e.g. responses to a questionnaire) are made on a single occasion across a group of subjects. Cross-sectional studies generally focus on a single group of people representative of the population of interest.
DIFFUSE NOXIOUS INHIBITORY CONTROL (DNIC)
Diffuse noxious inhibitory control describes a type of descending inhibitory control system in animals that is triggered by a noxious stimulus distant to the primary test stimulus. The term Conditioned Pain Modulation (CPM) describes activation of this system, wherein the test stimulus is used to assess the level of sensitivity while the ‘conditioning’ stimulus refers to the noxious stimulus used to activate DNIC.
As used when referring to an instrument used as an outcome measure, it is the ability of the instrument to discriminate between different levels of disease or clinical signs.
DEFINITIONS OF PAIN AND RELATING TO PAIN
An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. Note: The inability to communicate verbally does not negate the possibility that an individual is experiencing pain and is in need of appropriate pain-relieving treatment. Pain is always subjective. Each individual learns the application of the word through experiences related to injury in early life. Biologists recognize that those stimuli which cause pain are liable to damage tissue. Accordingly, pain is that experience we associate with actual or potential tissue damage. It is unquestionably a sensation in a part or parts of the body, but it is also always unpleasant and therefore also an emotional experience. Experiences which resemble pain but are not unpleasant, e.g., pricking, should not be called pain. Unpleasant abnormal experiences (dysesthesias) may also be pain but are not necessarily so because, subjectively, they may not have the usual sensory qualities of pain. Many people report pain in the absence of tissue damage or any likely pathophysiological cause; usually this happens for psychological reasons. There is usually no way to distinguish their experience from that due to tissue damage if we take the subjective report. If they regard their experience as pain, and if they report it in the same ways as pain caused by tissue damage, it should be accepted as pain. This definition avoids tying pain to the stimulus. Activity induced in the nociceptor and nociceptive pathways by a noxious stimulus is not pain, which is always a psychological state, even though we may well appreciate that pain most often has a proximate physical cause.
Pain that is obviously coupled with tissue injury, generally short-lived and can be considered protective in nature. Often defined as lasting less than 1 month, or less than 3 months.
Pain that is obviously coupled with tissue injury, generally short-lived and can be considered protective in nature.
Pain due to a stimulus that does not normally provoke pain.
Absence of pain in response to stimulation which would normally be painful.
Pain in an area or region which is anesthetic.
Chronic pain has defined as pain that lasts beyond the normal healing time, thus lacking the acute warning function of physiological nociception. Often defined on a temporal basis – pain lasting more than 3 months.
An unpleasant abnormal sensation, whether spontaneous or evoked.
Has been used to describe ‘good pain’, i.e. ‘adaptive pain’.
Increased pain from a stimulus that normally provokes pain.
Increased sensitivity to stimulation, excluding the special senses. Allodynia is suggested for pain after stimulation which is not normally painful. Hyperesthesia includes both allodynia and hyperalgesia, but the more specific terms should be used wherever they are applicable.
A painful syndrome characterized by an abnormally painful reaction to a stimulus, especially a repetitive stimulus, as well as an increased threshold.
Diminished pain in response to a normally painful stimulus.
Decreased sensitivity to stimulation, excluding the special senses.
Pain that occurs in the absence of ongoing noxious stimuli and does not promote healing and repair. Also referred to as ‘maldynia’
Pain that occurs in the absence of ongoing noxious stimuli and does not promote healing and repair. Also referred to as ‘maladaptive pain’
Pain in the distribution of a nerve or nerves.
Inflammation of a nerve or nerves.
Pain caused by a lesion or disease of the somatosensory nervous system. The presence of symptoms or signs (e.g., touch-evoked pain) alone does not justify the use of the term neuropathic.
Central neuropathic pain
Pain caused by a lesion or disease of the central somatosensory nervous system.
Peripheral neuropathic pain
Pain caused by a lesion or disease of the peripheral somatosensory nervous system.
A disturbance of function or pathological change in a nerve: in one nerve, mononeuropathy; in several nerves, mononeuropathy multiplex; if diffuse and bilateral, polyneuropathy.
The neural process of encoding noxious stimuli.
A central or peripheral neuron of the somatosensory nervous system that is capable of encoding noxious stimuli.
Pain that arises from actual or threatened damage to non-neural tissue and is due to the activation of nociceptors.
An actually or potentially tissue-damaging event transduced and encoded by nociceptors.
A high-threshold sensory receptor of the peripheral somatosensory nervous system that is capable of transducing and encoding noxious stimuli.
Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.
A stimulus that is damaging or threatens damage to normal tissues.
The minimum intensity of a stimulus that is perceived as painful.
Pain tolerance level
The maximum intensity of a pain-producing stimulus that a subject is willing to accept in a given situation.
An abnormal sensation, whether spontaneous or evoked.
Increased responsiveness of nociceptive neurons to their normal input, and/or recruitment of a response to normally subthreshold inputs.
Increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.
Altered responsiveness of nociceptive neurons in the central nervous system – can result in increased or decreased responsiveness.
Increased responsiveness and reduced threshold of nociceptive neurons in the periphery to the stimulation of their receptive fields.
see: blinded trial
A drug is defined as:
• A substance recognized by an official pharmacopoeia or formulary.
• A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
• A substance (other than food) intended to affect the structure or any function of the body.
• A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device.
• Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process.)
The extent to which an intervention works when introduced to the general population outside of the context of a controlled study.
EFFECT SIZE – (STANDARDIZED EFFECT SIZE)
A simple way to determine the degree of improvement (or otherwise) of a particular therapy after any placebo effect has been accounted for. The effect size is calculated as the ratio of the treatment effect (mean differences in treatment group minus differences in placebo group) to the pooled standard deviation of these differences.
The extent to which a treatment improves outcomes under controlled conditions (e.g. in the context of a clinical trial). The efficacy is related to the effect size documented in clinical studies.
EVIDENCE BASED MEDICINE
Evidence-Based Medicine is the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgement that individual clinicians acquire through clinical experience and clinical practice. By best available external clinical evidence we mean clinically relevant research, often from the basic sciences of medicine, but especially from patient centred clinical research into the accuracy and precision of diagnostic tests (including the clinical examination), the power of prognostic markers, and the efficacy and safety of therapeutic, rehabilitative, and preventive regimens. External clinical evidence both invalidates previously accepted diagnostic tests and treatments and replaces them with new ones that are more powerful, more accurate, more efficacious, and safer. Below is the hierarchy of study design. Designs at the top of the provided the greatest strength of evidence – least potential for bias, with study designs at the bottom of the list having the greatest potential for bias.
1. Meta-analysis of controlled trials
2. Systematic reviews of controlled trials
3. Interventional Analytic Studies (i.e. Controlled trials (RCT’s))
4. Observational Analytic Studies
• Cohort Studies
• Case Control Studies
5. Descriptive Studies
a. Case Series
6. Case Reports
7. Expert opinions
Pre-defined factors that exclude a subject from a trial or study.
GOOD CLINICAL PRACTICE
A 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.
A proposed mechanism that might explain a known fact or observation. A hypothesis may be tested by a well-designed research protocol.
The predefined characteristics that allow a subject to be entered for consideration for a trial.
The decision by a person or care-giver to give or not give permission for an action affecting them. The decision is based upon having all the information bearing on the situation including the advantages, disadvantages, and the various consequences involved.
KINETIC GAIT ANALYSIS
Kinetic gait analysis is a method of studying these forces using ground reaction forces. Essentially, kinetic gait analysis quantifies limping with regards to the force or pressure that the animal is willing to bear.
MINIMAL CLINICALLY IMPORTANT DIFFERENCE
A minimal clinically important (or relevant) difference (MCID) can be defined as the smallest difference in score on an outcome measure (e.g. pain, disability, quality of life), which is believed to be important or beneficial to the patient. This MCID can be used as a criterion to assess if a therapy has potential beneficial effects.
The induction or the worsening of symptoms induced by sham or active therapies
Outcome measures that are not susceptible to observation bias.
Observation bias occurs when knowledge of a study subject’s group allocation influences identification of relevant events during the study.
The effect of treatment on a patient, which may be measured in a number of ways. Objective measures (outcomes) are independent of subjective evaluation, e.g. biological blood tests; ground reaction forces. Subjective outcomes are based on the experience or opinion of the patient, or caregiver.
The methods used to measure outcome – in this case pain or dimensions impacted by pain.
Humans or owned animals that are under medical care for, or have, a disease condition.
The composite of an animal’s observable or measured characteristics or traits, such as its morphology, development, biochemical or physiological properties, or behavior.
A sham or non-active treatment that is administered during a trial.
This effect represents a beneficial response to an inert treatment that exists for reasons unrelated to the actual treatment given, but depends on the context in which the treatment is provided and the patient’s experience and expectations. Strictly, the ‘placebo effect’ is the effect of administering the placebo over and above any effect of no intervention at all.
This is where a caregiver’s belief that the animal is receiving an effective medication alters the animal (e.g. by their interaction with the animal) and manifests as a real beneficial effect for the animal.
A study where patients are selected before any data collection starts.
The defined, and usually written, plan or set of steps to be followed in a study.
QUANTITATIVE SENSORY TEST (QST)
Quantitative sensory testing involves the application of a stimulus at a peripheral site, and measurement of the time to reach an endpoint or elicit a reaction. In humans, various endpoints can be measured (first detection, noxious, maximum tolerated), but in veterinary medicine, the response is generally defined as a reaction such as withdrawal, or vocalization, or some other sign of central appreciation of the stimulus. Threshold refers to the point at which the response occurred, and is measure in units of the stimulus (for ramped stimuli) or time (for fixed stimuli).
RANDOMISED CONTROLLED TRIAL (RCT)
(Synonym: randomized clinical trial) - An experiment in which investigators randomly allocate eligible subjects into (e.g. treatment and control) groups to receive or not to receive one or more interventions that are being compared. The results are assessed by comparing outcomes in the treatment groups and control groups.
How easy a questionnaire is to read, based on expected reading ability of different grade levels in the US education system.
The reproducibility of the results of a tool administered on different occasions over which time a subject should not have changed.
RELIABILITY: INTERNAL CONSISTENCY
When the tool is a questionnaire, its internal reliability (or consistency) is based on the results from a single administration of the tool to a cohort with the trait to be measured and is represented by correlations among the questions in the tool with and across domains.
The ability of an instrument (method, questionnaire etc.) to measure a significant change in what is being measured (e.g. pain) in response to an intervention known to be effective.
The provision, usually in a clinical trial setting, for transferring a subject to a ‘rescue’ analgesic in the event that the subject is not responding appropriately to the treatment being administered (whether placebo or active).
A study where patients are selected then their medical records are used to find out what has happened to them.
Outcome measures that are susceptible to observation bias.
Measurement where the instrument itself is not susceptible to observation bias, but how the instrument is used in the study can influence the results, and thus the results can be susceptible to observation bias (e.g. accelerometers per se are objective but the caregiver awareness of group allocation could influence the amount of activity they encourage or discourage in their dog thus affecting the results of the study)
The ability of a test to correctly identify those individuals with the condition – true positives. Thus a highly sensitive test gives few ‘false-negative’ outcomes.
In research, statistical tests determine the likelihood that a result arose by chance. The scientific norm is p<0.05 for statistical significance
The ability of a test to correctly identify those individuals without the condition – true negatives. Thus a highly specific test gives few ‘false-postive’ outcomes.
Animals being used in a study; can be human or non-human, and may be patients (diseased) or normal.
Outcome measures that are susceptible to observation bias.
Evidence consisting of one or more adequate and well-controlled studies, such as, a study in a target species, a study in laboratory animals, a field investigation, a bioequivalence study, or an in vitro study, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and reasonably be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.
Refers to whether the claims (e.g. about what an instrument measures) can be justified and supported.
VALIDITY – (external)
The extent to which the research findings can be generalised to the wider population of interest and applied to different settings – a.k.a generalizability.
VALIDITY – (internal)
The ability of an instrument (method, questionnaire) to measure what it is intended to measure. Or the validity of specific study results based on the study design and implementation.
VALIDATED OUTCOME MEASURE
There is no defined endpoint of validity. A valid instrument is one where more research and information would not substantially change the inference about the function of the instrument. An valid outcome measure is one that shows the following components of validity:
VISUAL ANALOGUE SCALE (VAS)
This is a psychometric response scale which can be used in questionnaires. It is used for subjective assessment of the intensity of characteristics (pain) that cannot be directly measured but which are believed to range across a continuum of values. It consists of a line of usually 100mm in length, with descriptive tethers at each end. The addition of interval marks or other descriptors or numbers along the length move the VAS towards an interval scale.
A von Frey hair is a type of aesthesiometer designed in 1896 by Maximilian von Frey. Von Frey filaments rely on the principle that an elastic column, in compression, will buckle elastically at a specific force, dependent on the length, diameter and modulus of the material. Used to test mechanical sensitivity. The term von Frey is also used to refer to modern fixed versions of von Frey hairs – usually a pipette-tip like end attached to a load cell.