Unit Ill: PreClinical Phase ) C Q Preclinical Phase Introduction: Preclinical Phase > Biologic activity test, chemical synthesis, formulation studies, stability testing and safety test on animal and human subjects >preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.al < > C Q Insert your topic here Preclinical testing includes: 1. Discovery testing to ensure biological activity in vivo 2. Chemical synthesis and scale-up to ensure adequate quantities of high purity can be made 3. Formulation development and stability testing to characterize various chemical properties, develop the initial drug delivery system, and determine the stability of the compound 4.. Animal safety testing to ensure limited toxicities of the lead agent.arto © + C Q Insert your topic here > GLPs are followed > Qualifications of personnel Preclinical : Clinical > SOPs : > MOA of drug in animal COLIN models, specificity, DOA, SAR : > High level of purity (>0.1%- characterized and tested for toxicity)SCs Preclinical phase |X fag © > @ Q Insert your topic here > Physicochemical prop of active compound > Dev. of DDS to be used in human testing a > Animal testing >> ADME > S/E and tox are noted > Tox in humas testing>> min. of 2 weeks > at least 2 animal species: one rodent and one non rodentSom Tc Prectinicat phase © > @ Q Insert your topic here > same route intended for humans > aerosol, nasal, buccal > dosing studies>>> no-observed- adverse-effect levels (NOAELs) - used to determine initial phase 1 clinical trial dosage levels on a mass API per mass per patient bases > plasma concentration x i=== {Senemavc of the new arog approval process m the Une States. For Me-reatering nesses Such as ‘cancer, patents enrolled in Phase I studies may ser from the dsease)Od Drug Safety xe Evaluation © + C Q Insert your topic here X< Drug Safety Evaluation >In vitro tests are experiments conducted in the lab, usually carried out in test tubes and beakers (“vitro” is “glass” in Latin) > In vivo studies are those in living cell cultures and animal models (“vivo” is “life” in Latin). >" First scale up"Od Toxicity Testing = X am © + C Q Insert your topic here xX Toxicity Testing > reveals the species-, organ-, dose- specific toxic effects on various biological system (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals.a md Toxicity Testing ae SX Toxicity Testing > Toxicants are classified based: © > @ Q Insert your topic here a. chemical nature b. mode of action c. class (exposure class and use class) Exposure class= food, air, water or soil Use class= drugs of abuse, therapeutic drugs, agriculture chemicals, food additives, pesticides, plant toxins, cosmeticsCd Toxicity Testing = X am © + C Q Insert your topic here SX Toxicity Studies: Acute Toxicity testing “> carried out to determine the effect of a single dose on a particular animal species > carried out with two different animal species (one rodent and one nonrodent) > investigational product is administered at different dose levels, and the effect is observed for 14 days. > All mortalities caused by the investigational product during the experimental period are recorded and morphological, biochemical, pathological, and histological changes in the dead animals are investigated.SC cd Toxicity Testing Xm © + C Q Insert your topic here Toxicity Studies: Acute Toxicity testing Acute toxicity testing for inhalation > performed for aerosol-like preparations. > Rats are the most preferred animal species. > (temperature preferably 22°C + 2°C). They are maintained in an air flow of 12-15 air changes per hour with adequate oxygen (19%/h). > The animal is exposed to the test substance for a minimum of 4 h, and then it is monitored for 14 days. > Food is withheld during the exposure period, and water may be withheld under certain conditions.SC Sd Toxicity Testing XJ © + C Q Insert your topic here Toxicity Studies: Acute Toxicity testing Acute toxicity testing for inhalation >. During the observation period, the animal is observed for tremors, convulsions, salivation, diarrhea, lethargy, sleep, and coma. > Mortality during the exposure and observation period is noted. > At the end of the study, the animals are sacrificed, and pathological changes are evaluatedOd Toxicity Testing = X am © + C Q Insert your topic here Toxicity Studies: Acute toxicity testing for topical preparations > eye irritation test and skin irritation test > Draize tests- used to measure the harmfulness of chemicals and pharmaceutical substances in rabbits and guinea pigs. > In the eye irritation test, 0.5 ml of a test substance is administered to an animal's eyes, and the animal is restrained for 4 h. Redness, swelling, discharge, ulceration, hemorrhage, and blindness are assessed and monitored for 14 days.Sm Cm Toxicity Testing = X am © > C Q Insert your topic here ‘S€ Toxicity Studies: Acute toxicity testing for “ “topical preparations Draize TestOd Toxicity Testing = X am © + C Q Insert your topic here Toxicity Studies: Acute toxicity testing for topical preparations > In the skin irritation test, 0.5 g of a test substance is applied to the surface of an animal's skin. During the observation period (14 days), signs such as erythema and edema are assessed. Some alternative in vitro testing methods are available that can be used in place of the Draize eye irritancy test.ao Toxicity Testing Xm © + C Q Insert your topic here Toxicity Studies: Acute toxicity testing fi for topical preparations —_SC cd Toxicity Testing XJ © + C Q Insert your topic here xX Toxicity Studies: Skin sensitization tests >carried out using the guinea pig as a model > Skin sensitization is assessed using the Draize test, open epicutaneous test, optimization test, split adjuvant test, guinea pig maximization test (GPMT), Buehler test, and murine local lymph node assay (LLNA) > In the LLNA test, the test substance is applied on the surface of the ears of a mouse for three consecutive days, and the proliferation of lymphocytes in the draining lymph node is measured at the end.Sm Cm Toxicity Testing = X am © > C Q Insert your topic here ‘S€ Toxicity Studies: Skin sensitization tests . - Medscapes www medscape.com Local lymph node assay Days 1,283. ay 6— inject apply chemical thymine x used to assess submicroscopic changes in the base sequence of DNA, chromosomal aberrations, and structural aberrations in DNA including duplications, insertions, inversions, and translocations. > The test generally includes a bacterial reverse mutation assay.eee a) Toxicity Testing Xfm © > @ Q Insert your topic here ‘S€ Toxicity Studies: Mutagenicity Testing ‘Ames Test oo cw Plate roaibate (— Ratliver Extract Ss — es Possible CConntrol Pate Media with ‘Minimal Histidine Ee smo fl —- GD =6 Histidine) Sz eguires AHigh Number of Revertants(his-tohis+) suggests the Mutagen ‘causes MutationSC Cd Toxicity Testing Xfm © > C Q insert your topic here xX Toxicity Studies: Carcinogenicity Testing > Both rodents and non rodent animal species may be used > During and after exposure to test substances, the experimental animals are observed for signs of toxicity and development of tumors. > If these are not found, a test may be terminated after 18 months in the case of mice and hamsters and after 24 months with rats.SC Cd Toxicity Testing Xfm © + C Q Insert your topic here xX Toxicity Studies: Carcinogenicity Testing > f the animals are healthy, hematological analysis is performed after the 12 months and the 18 months, respectively, and the study is terminated. >The animals are sacrificed, and gross pathological changes are noted and histopathological studies are carried out on all the tissues.eee a) Toxicity Testing Xfm © > @ Q Insert your topic here SX Toxicity Studies: Carcinogenicity Testing CPMPIICH/299/95 Testing for Carcinogenicity of Pharmaceuticals One long-term study , ‘Shortimedium- Basic -term study Principle (insight to care. endpoints) neo-natal: transgenic _ [One other study long-term study 2nd speciesEthical Considerations in Human and Animal Experimentation12/21/2018 CARE, MANAGEMENT AND USE OF LABORATORY/ RESEARCH ANIMALS Pa ene ae INTRODUCTION — Why do we use animals? + Teaching, + Initial phase of research ‘+ Non-animal vs Animal models ‘THE THREE Rs IN RESEARCH A = the use of non-sentient material to REPLACEMENT. replace methods which use conscious living vertebrates REDUCTION - minimizing the number of animals used to obtain information A ~ decrease incidence or severity of, inhumane procedures applied to the animals12/21/2018 Prropucron — © ANIMAL WELFARE VS ANIMAL RIGHTS © Animal welfare + Human responsibilty that encompasses all aspects of animal well being, including proper housing, management, nutrition, disease prevention and treatment, humane handling, and when necessary, humane euthanasia + Well-being, characterized as the fulfillment of needs © Animal rights + Animals have the same mora rights human beings or in part because they have many ofthe same mental capabilities and activities as people ‘Irropuct To © The World Veterinary Association (WVA) has adopted an animal welfare policy, which includes the following statement: + “We do not accept the view that animals have specialized rights san entity on their own, We believe that animals can benefit more from the point of view that man is responsible for the provision of animal ‘welfare, rather than from the view which promotes animal rights alon © Anticruelty position freedom from pain or suffering © The only very strong interest that nonhuman animals. possess is an interest in not experiencing pain or suffering - or, if they must undergo some pain or suffering in their use by people, in not experiencing ‘unnecessary pain or suffering.12/21/2015 ERNME! © Bureau of Animal Industry (BAI) spine Association for Laboratory Animal Science (PALAS) © Committee on Laboratory Animal Resources Development and Standardization (LARDS) © Protected Areas and Wildlife Bureau (PAWB) © Philippine Council for Health Research and Development (PCHRD) Laws © R.A. 8485 ~ Animal Welfare Act © DA.A.O. No. 40 ~ Rules and Regulations on the Conduct of Scientific Procedures Using Animals | PRINCIPLES @ PROTOCOLS IN ANIMAL CARE AND USE » Rationale * Relevance to human oranimal health * Good of society * Unnecessary duplication of research © Species used in research: + Rodents mouse, rat, gerbil, hamster, guinea pig, + Lagomorphs - rabbit + Carmivores ~ ferret, dog, cat + Ungulates pig cattle, sheep, goat, horse + Non-human primates - monkeys, apes © Appropriate species, quality, number oranimals * Justified statistically + Alternatives (les invasive procedures, other species, isolated ‘organ preparation, tissue culture, computer models)12/21/2018 Preis & PROTOCOLSIN ANIMAL CARE AND USE © Appropriate sedation, analgesia or anesthesia © Minimal discomfort, pain and stress + Best welfare = best science + What is meaningful to the animal + Aim at well-being (not mere absence of distress) © Appropriate animal husbandry © Conduct of experimentation by or under the close supervision of qualified and experienced persons © Conduct of multiple major operative procedures © Intervention, removal or euthanasia if stressful outcomes are anticipated PRINCIPLES & PROTOCOLS IN ANIMAL CARE AND USE © Postprocedure care © Method of disposal or euthanasia © Safety of working environment © Know and anticipate what you are going to do before the start of the research.12/21/2015 PHYSICAL RESTRAINT © Restraint devices are not normal methods of housing © Not to be used simply asa convenience in handling © Period of restraint should be minimum © Train animals to adapt to restraint devices © Observe animals at appropriate intervals © Provide veterinary care in case of injury or illness due to restraint12/21/201512/21/2015 RESTRAINT OF RATS12/21/201512/21/2015 \SURGICAL PROCEDURES ——— ‘Multiple major surgeries on an animal are discouraged + Permitted if scientifically justified * Cost savings alone is not an adequate reason © Payattention to animal well-being through continuing evaluation of outcomes FOOD OR FLUID RESTRICTION © Should be scientifically justified © Monitor physiologic or behavioral indexes © Use least restriction to achieve scientific objective © Use highly preferred food instead of restriction for positive reinforcement12/21/2015 OTHER CONSIDERATIONS © Veterinary care © Personnel qualifi © Personal hygiene © Occupational health and safety of personnel © Hazard Identification and Risk Assessment © Facilities, Procedures and Monitoring © Personal protection © Medical evaluation and preventive medicine for personnel sand training JALEN AND MANAGEMENT © Species, strain and breed of animals © Sex, age, size © Maintained singly or in groups * Ability to form social groups through sight, smell, contact © Design and construct of housing © Availability and suitability of enrichments © Project goals and experimental design © Intensity of animal manipulation and invasiveness © Presence of hazardous materials © Duration of holding period 1012/21/2018 PHYSICAL ENVIRONMENT © Microenvironment ~ primary enclosure + Immediate surroundings, temperature, humidity, air composition. = Can induce changes in metabolic and physiologic processes * Macroenvironment ~ secondary enclosure + Room, barn, outdoor habitat HOUSING © Naturalistic environments © Sheltered or outdoor housing, © Primary enclosures + Allow normal behavior and physiologic needs + Allow social interaction, development of hierarc + Adequate ventilation + Allow easy access to food and water and servicing + Provide a secure environment (no escape and no injury) + Allow observation with minimal disturbance u12/21/201512/21/2015 a. ACE RECO!12/21/2018 SPACE RECOMMENDATIONS ci LATION ; © Exposure to temperatures above or below the optimum ranges without shelter or protective mechanisms might produce clinical effects ion should supply adequate oxygen, dilute gaseous contaminants, remove thermal loads © Can differ considerably between primary and secondary enclosures12/21/2018 ILLUMINATION © Light can affect physiology, morphology, behavior © Sufficient lighting for animal well-being and good housekeeping practices © Provide adequate vision and neuroendocrine regulation of diurnal and circadian cycles © Management practices to provide animals with ways to, modify their own light exposure by behavioral means NOISE © Separation of human and animal areas to minimize disturbances © Noisy animals should be separate from quieter animals © Some effects of loud noise + Eosinopenia, increased adrenal weights, infertility, high blood pressure © Some species are sensitive to frequencies of sound inaudible to humans + Example: video display terminals 1512/21/201512/21/2015 | BEHAVIORAL MANAGEMENT © STRUCTURAL ENVIRONMENT * Cage furniture, enrichments, complexities ‘+ Depending on the animal species © SOCIAL ENVIRONMENT. * Physical contact and communication + Non-contact communication through visual, auditory and olfactory signals + Naturally territorial vs communal animals. + Notall social species can or should be maintained socially © ANIMAL ACTIVITY + Vertical dimension should be considered «= Forced activity should be avoided. 712/21/2015 HUSBANDRY » FOOD, + Palatable, clean, nutritionally adequate ‘+ Animals with easy access to feeders and minimize contamination with urine and feces ‘ Adequate access to all animals housed in groups + Provide wood chips, teats, ete (depending on species) lean and enclosed storage (off the floor) = Check shelf-life of food. 1812/21/2018 sea © WATER * Adlibitum. + Considerany possible water treatments and effects + Daily inspection for cleanliness, maintenanceand proper ‘operation * After refilling feeders and waterers, they should be returned to the same cages they were taken fro » BEDDING + Appropriate material, sufficient to keep animals dry, should ‘not come into contact with water tube and feeders man TATION — » BEDDING CHANGE + Daily, weekly, reproductive considerations » CLEANING AND DISINFECTION OF PRIMARY ENCLOSURES = Chemicals, hot water or both «= Frequency depends on type of cages © CLEANING AND DISINFECTION OF SECONDARY ENCLOSURES © WASTE DISPOSAL, © PEST CONTROL « Preferably via non-toxic means » EMERGENCY, WEEKEND AND HOLIDAY CARE, 1912/21/2015 2012/21/2015 OtHer CONSIDERAT ONS” » ANIMAL PROCUREMENT AND TRANSPORTATION + Important to procure animals from reputable sources, accredited laboratories (NOT FROM PET SHOPS!) ‘ Minimize transit time and risk of zoonoses, avoid ‘overcrowding and environmental extremes += Provide adequate protection, food and water © QUARANTINE, STABILIZATION, SEPARATION = Length of time of stabilization depends on species, type and duration of transport, intended use © SURVEILLANCE, DIAGNOSIS AND TREATMENT OF DISEASE * Appropriate veterinary care when needed a12/21/2018 Figure 21.11 Disposable anspor cape of cardboard the inside ‘vere with plas, ponte wth wie mash and ers Phot SHIPPING CONTAINERS 2“TRANSPORTATION12/21/2015 RULE OF THUMB: © 10% of the animal's weight is blood. © The maximum amount of blood that can be collected is10% of the blood volume of the animal. © Or1% of the body weight of the animal. 2s12/21/2015 ANIMAL CARE AND USE STATEMENT (Protocol Review Form) © Should be accomplished! as part of the research proposal - research can only proceed once this is approved © Explains in full detail all aspects of the research that involves animals © Makes sure all groups know what they will be doing before the actual conduct of the research, AL CAI (Protocol Review Form) |. PROCEDURE(S) OR TITLE OF RESEARCH/STUDY 1). PURPOSE / OBJECTIVES Ul, DURATION OR TIMEFRAME - excluding quarantine but including conditioning time 1. RESPONSIBLE PERSON / PRINCIPAL INVESTIGATOR. - Name/s and qualifiction BACKGROUND AND SIGNIFICANCE OF PROCEDURE OR RESEARCH - Include biomedical characteristics of the animals that are essential to the research & indicate related studies with the proposed animal model 26(Pre vi mmpne> 12/21/2015 JAL CARI otocol Review Form) DESCRIPTION OF METHODOLOGIES / EXPERIMENTAL DESIGN Species and type of animal Source of animals Reason/bass for selecting animal species Sex, ageand numberof animals (justly number) Quarantine and/or conditioning process Animal care procedures Cagetype # of animals percage Cleaning method Roomtemp. humidity, ventilation, lighting Diet, feeding and watering method AL CAI (Protocol Review Form) a H Experimental or animal manipulation methods General description (including conditioning method) Dosing method. Expected outcome, effets, adverse side eects Specimen or biological agent (Frequency, volume, route, and ‘method of restraint) Animal examination procedures Use of anesthetics Surgical procedures Euthanasia Is there a non-animal model applicable? Ifso, provide reasons for not using it. aD12/21/2018 AL CAI (Protocol Review Form) Itis expected that the study will be conducted. according to the approved protocol Obtain approval from the IACUC prior to making any changes affecting the protocol REFERENCES » PALAS Code of Practice for the Care and Use of Laboratory Animals in the Philippines © Guide for the Care and Use of Laboratory Animals © The UFAW handbook on The Care and Management of Laboratory and Other Research Animals 2312/21/2015 ‘&e (082) 286 6063 0920 546.4211 (smart) (0922 208 1610 (sun) docbayani@gmail.com @ @docbayani @ wn facebook com/DocBayani ‘© http://wwn.docbayani.com 29SC NUAIN AEA e TON AN CAT a0 tae OF HUMAN SUBJECTS (CLINICAL PHASE) IN DRUG TESTING>< “When people are invited to participate in research, there is a strong belief that it should be their choice based on their understanding of what the study is about, and what the risks and benefits of the study are,” said Dr. Christine Grady, chief of the NIH Clinical Center Department of Bioethics, to Clinical Center Radio in a podcast+ Social Value >< Informed consent Essential information for participants Documentation of consent Waiver of the informed consent Renewing the consent > Vulnerability of Research Participants > Risks, Benefits and Safety “> Privacy and Confidentiality of Information “© JusticeRe NTA AOR CCTV RY< LEARNING OBJECTIVES: +a. define clinical trials -- b. describe the design and types of clinical trials + ¢. discuss the importance of conducting clinical trials in drug discovery>< CLINICAL TRIALS -- According to WHO -- type of research that studies new tests and treatments and evaluates their effects on human health outcomes + carefully designed, reviewed — and completed, and need to be approved before they can start. ‘ People of all ages can take part in clinical trials, including children.> CONSIDERATIONS FOR CLINICAL TRIALS 1s: P’cologic profile is equal or better than existing competitors 2°4: Address unmet medical or improve therapy 3'¢: Market potential sufficient to sustain profitability4th: Risk factors are assessed Sth: Potential expenses 6th: Success in the marketplace>< WHAT 1S CLINICAL RESEARCH? -- Clinical trials are conducted to collect data regarding the safety and efficacy of new drug and device development. +» “Clinical research” refers to studies, or trials, that are done in people.Sap aLTaNUNTea UUM ITaNNTaS=< TRIAL OBECTIVES +» Phase I- limited to determining toxicity at a range of dosages * Terminal illnesses- efficacy assestment - Phase Il and Ill- Clinical efficacy in large sample of patients -- Phase IV- Assess efficacy and side ffects in specific patient population>< COMPONENTS OF A TRIAL OBJECTIVE 4 -- Approach of the trial (to compare, asses and evaluate) Specific disease ‘Types of patients ~ Drug therapy(ies) ‘ Dosage -+ Purpose ( safety, effecicacy,p'kinetic properties) Clinical endpoints (biologic measures, rate of cure, cost effectiveness)>< CLINICAL TRIAL OBJECTIVES -- Determination of sample size ~ Recruitment - Measurements of effects of drugs - Feasibility of the trials (trial duration and costs) - Data collection procedures and statistical analyses must be established during planningSans>< DESIGNING CLINICAL TRIALS + Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol that is developed by the researcher or manufacturer.+. Who qualifies to participate (selection criteria) >< How many people will be part of the study - How long the study will last Whether there will be a control group and othe ways to limit research bias - How the drug will be given to patients and at what dosage What assessments will be conducted, when, and what data will be collected - How the data will be reviewed and analyzed-- Phase I- all patients receives the drug> unblinded, open label trial ~ Phase Il and II- drug is compared to placebo or alternative tx, patients receive one of the tx during the entire trial> parallel designParallel Study Vs. Crossover Study Design biotechPrimer Parallel Study is when two groups of treatments are given so that one group receives ony placebo or standard of cae treatment while another group receives only the drug, Crossover Study is when each subject receives a placebo, folowed by a washout period, ad then receives the drug or visa versa Randomization Pecan Baseline Dug Wash out period Placebo Placebo Drug Drug>\< PARALLEL DESIGN -- Factorial design- used to compare different types and combinations of drug therapy -- Allows comparisons between single drug therapies and combination of two drugs combined>< TYPE OF TRIAL -- Crossover design- allows patients to receive more than one drug treatment or dosage level during the course of the trial - Assumption: drug therapy does not have a carry-over effect between the different tx period.-- “Washout period”> placebo or no medication + Depends on DOA or rate of elimination of trial drugs -- Issue: sufficient to eliminate carry-over effect-- During the washout period- trial data and clinical measures are collected to assess the impact of previous tx -- Considered as baseline data for subsequent tx -- Efficient in regards to no. of patients required to collect a data>1< POSTMARKETING SURVEILLANCE (PHASE LV) 4 -- Non-experimental (observational) -- Case -control and Cohort- drug therapy is not assigned by the researcherE} CUTER EN |-- Control of the intervention- critical component of the trial - Three levels: Assignment of the patients to the intervention 6. Application of the intervention c. Measurement of the trial outcomes wo>.< ASSIGNMENT OF THE INTERVENTION -- Cause and effect of the relationship between the drug therapy and clinical outcomes can be established -- Accomplished through randomization- computer programs or number lists> assures that assignment to tx intervention are unbiased-- In most trials, patients have equal chance of receiving each tx Some trials is designed to have imbalance in tx assignment. Ex. 2:1 or 3:1-- Stratified randomization- used to adjust for potential differences in response between specific patient groups or trial sites. + Characteristics of concern ( type or severity of illness, gender, age, race or study site)- patients are randomized base on their strata.>< STRATIFIED RANDOMIZATION t -- This assures equal numbers of patients with this characteristics are assigned to each trial tx.Stratified Random Sampling Illustrated rao Canning _/” ten fren ipa to Population=< BLOCKED RANDOMIZATION -- Sample size for a specific number of patients is established so that equal number of patients are assigned to each treatment group. * It avoids imbalance in enrollment between treatment groups as trial progresses.Intervention Control Block Randomization Keep size of each group similar over entire stud: Block 3>< APPLICATION OF INTERVENTIONS -- Clinical protocols is used to control the application of intervention - Designed to address most potential contingencies that occur during the trials -- Protocol adherence is monitored throughout the trial-- Deviations form protocol are documented and discussed - Repeated deviations in the protocol by a particular site may result in disciplinary action such as removal from participation in the trial.>< MEASUREMENT OF TRIAL OUTCOMES -- Use of special type of measurement tool or instrument is used to measure outcomes, training of all trial personnel regarding use of the instrument. is performed prior to trial start-up. - Use of an Assessment toolvA SELECTING THE TRIAL eonsic Using inclusion (identify patient groups specified by trial objectives) and exclusion criteria (eliminate patients who might be harmed, unlikely to survive, who will not receive the tx due to allergy, concomitant illness or contraindication) + Phase I- healthy volunteers ( life threatening diseases) + Phase Il and Ill- w/ disease, patients who will likely benefit from the studyi FEASIBILITY OF CONDUCTING malar>< FEASIBILITY -- Dependent: trial purpose, intended application of trial results and access to trial sites and patients - Overall trial cost and timelines primary objective and sample size+ Trial purpose: type of outcome + Outcomes of mortality- lengthy observation + Outcomes that intended to be generalized- need broad inclusion and exclusion criteria +- Trial outcome measurements affects the type and quantity of data required, additional testing requirements>.< FEASIBILITY -- Number of patients available, percentage likely to meet the inclusion and exclusion criteria - Contract Research Organization (CROs)- helps identify patients and provide access to patients7 MUALUIGMSAET DI>< BLINDING -- Involves disguising of drug therapy to the patient and health professionals to minimize bias ~- Controlled trial + Single, Double, Triple>< BLINDING +» Single blinding- only patient is unaware of which tx grouped they are assigned - Double blinding- both patient and health professional evaluating the effect and collecting data are unaware of trial drug assignment - Triple blinding- additional blinding of the biostatistician and Data Safety and Monitory Board > comparative safety and efficacy>< BLINDING -- Achieve by developing dosage forms of active and placebo that are indistinguishable (size,shape, etc) - Blinding must not significantly alter the drug release characteristics, physical stability of dosage forms, chemical stability of active component>< BLINDING +. Invitro tests for dissolution -- Labeling used is indistinguishable -- “Double dummy” approach- involves preparation of a separate matching placebo for each drug product - Disadvantage- affect pt. adherenceyears>< TRIAL DRUG PACKAGING Drugs are package to: Meet trial requirements Maintain the blinding Minimize the chances for dosing errors Enhance patient adherence to the therapeutic regimen 5. Maintain drug potency/stability BRWN>< TRIAL DRUG PACKAGING +- Package sizes ( count per bottle and number of bottles per kit) are designed to meet trial requirement of dosage adjustments, clinic visit period, visit window and dosing frequency>< TRIAL DRUG PACKAGING -- Helps maintain the blinding of study - Database is maintained which provides correspondence between bottle number and treatment assigned -- Complicated dosage regimen- blister card dosage is used- help improved adherence and direct/timely feedback‘cs him coating mn capmie and cower orignal douage torn Recor ct tam See tomomay erent fe opt "rHectg pater tego srtersive of ‘douage form may be itterent from ongmal Vp aeeeaping So formation, ‘ese ees eee Teme consuming and ‘mut reat Tray alte relma + Rea teen eens mtemaned encanto ser + Tables are Hat a | | Grinding and re tatieting Grinding and rman orga downge form “Sthokutiom can net verity weary Cred or embonsnd tabiees or oF cape eee seer em me tecaetem vena 20 rmatc erg i Beans coe + Cannot be 2 Bee: 2 preserves orginal Prormaceuteal Removal of martina Over ereapusiating i Ghinding and re ercapwlating i He bl separa gradient tom carne solution without ate Kaagied Coen Carvey G tier Mi Golrmey Ladera + Prom ing Veni, THFr REGULATIONS GOVERNING ___ CONDUCT OF CLINICAL TRIAL| Institutional Review Board (IRB) - asses trial protocol Informed consent Health Insurance Portability and Accountability Act of 1996 (HIPAA) - provides that patients be informed of their rights to maintain the privacy of health information &ANDAR E SNe 9 ETM AS OR OR UCT ome An>< INTENTION TO TREAT ANALYSIS (ITA) -- It means that even if the patient has stopped taking the medication, did not complete the assigned tx, or has been switched to an active alternative therapy, the data from the patient is included in the original tx group to which pt. is randomized.>< INTENTION TO TREAT ANALYSIS (ITA) -- Lessen the likelihood of finding a difference between the treatments + Itmore analogous to what happens outside the clinical trial situation. +» Itis the statistical feature of clinical trialssic ADJUSTMENT 10 MULTIPLE COMPARISON t -- Lowering the statistical boundary at which the researcher will consider the results significantly different>< SUBGROUP ANALYSIS -- Once data is obtained, researchers re- analyzed data from different perspectives - Ex: dividing the data into several different patient groupss\< Potential causes of deceptive findings: 1 w Trial was not designed to assure there was adequate sample size for the subgroup analysis Potentially confounding variables were not measured or controlled Insufficient theoretical underpinnings for the testTHE END