Clinical Trials + Antidotes - Hanouts, By Sir Irfan Hamid

7/30/2019 Clinical Trials + Antidotes - Hanouts, By Sir Irfan Hamid

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Clinical Pharmacy By Sir. Irfan HamidLecture: Clinical Trials & Antidotes

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CLINICAL TRIALSFOOD AND DRUG ADMINISTRATION (FDA):

The U.S. Department of Health and Human Services agency responsible for ensuring thesafety and effectiveness of all drugs, biologics, vaccines, medical devices, including thoseused in the diagnosis, treatment, and prevention of HIV infection, AIDS, and AIDS-relatedopportunistic infections.

CLINICAL TRIALS OVER VIEW

Discovery/

Preclinical

Testing

File

IND

at

FDA

Phase 1 Phase 2 Phase 3

File

NDA

At

FDA

FDA Phase 4

Years 6.5 1.5 2 3.5 1.5

Additional

post-

marketing

testing

required by

FDA

Test

Population

Laboratory

and animal

studies

20 to 100

healthy

volunteers

100 to 500

patient

volunteers

1,000 to 5,000

patient

volunteers

Review

process/

approval

Purpose

Assess

safety,

biological

activity, and

formulations

Determine

safety and

dosage

Evaluate

effectiveness

,

look for side

effects

Confirm

effectiveness,

monitor

adverse

reactions from

long-term use

Success

Rate

5,000

compounds

evaluated

5 enter trials 1 approved

WHAT IS CLINICAL TRIAL?

A clinical trial is a research study to answer specific questions about vaccines or newtherapies or new ways of using known treatments.

Clinical trials (also calledmedical research and research studies) are used to determinewhether new drugs or treatments are both safe and effective.

TERMINOLOGIES

Approved drugs:In the U.S., the Food and Drug Administration (FDA) must approve a substance as adrug before it can be marketed.


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The approval process involves several steps includinga) Pre-clinical laboratory and animal studiesb) Clinical trials for safety and efficacy,c) Filing of a New Drug Application by the manufacturer of the drugd) FDA review of the applicatione) FDA approval/rejection of application

Control group:The standard by which experimental observations are evaluated.In many clinical trials, one group of patients will be given an experimental drug ortreatment, while the control group is given either a standard treatment for the illness ora placebo.

Controlled trials:Control is a standard against which experimental observations may be evaluated.

In clinical trials, one group of participants is given an experimental drug, while anothergroup (i.e., the control group) is given either a standard treatment for the disease or aplacebo

Data Safety And Monitoring Board (DSMB):An independent committee, composed of community representatives and clinicalresearch experts, that reviews data while a clinical trial is in progress to ensure that

participants are not exposed to undue risk.A DSMB may recommend that a trial be stopped if there are safety concerns or if thetrial objectives have been achieved.

Enrolling:The act of signing up participants into a study. Generally this process involvesevaluating a participant with respect to the eligibility criteria of the study and goingthrough theinformed consentprocess

Informed consent:The process of learning the key facts about a clinical trial before deciding whether or notto participate. It is also a continuing process throughout the study to provideinformation for participants. To help someone decide whether or not to participate,the doctors and nurses involved in the trial explain the details of the study.

Inclusion/exclusion criteria:The medical or social standards determining whether a person may or may not beallowed to enter a clinical trial.

These criteria are based on such factors asAge, gender, the type and stage of a disease, previous treatment history, and othermedical conditions. It is important to note that inclusion and exclusion criteria arenot used to reject people personally, but rather to identify appropriate participantsand keep them safe.
http://clinicaltrials.gov/ct2/info/glossaryhttp://clinicaltrials.gov/ct2/info/glossaryhttp://clinicaltrials.gov/ct2/info/glossaryhttp://clinicaltrials.gov/ct2/info/glossary


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Institutional Review Board (IRB):a) A committee of physicians, statisticians, researchers, community advocates, and

others that ensures that a clinical trial is ethical and that the rights of studyparticipants are protected. All clinical trials in the U.S. must be approved by an IRBbefore they begin.

b) Every institution that conducts or supports biomedical or behavioral researchinvolving human participants must, by federal regulation, have an IRB that initiallyapproves and periodically reviews the research in order to protect the rights ofhuman participants.

Intent to treat:Analysis of clinical trial results that includes all data from participants in the groups towhich they were randomizedPrimary interventions being studied are Drug, Gene Transfer, Vaccine, Behavior,Device, or Procedure.

Investigational new drug:A new drug, antibiotic drug, or biological drug that is used in a clinical investigation. Italso includes a biological product used in vitro for diagnostic purposes.

Masked:The knowledge of intervention assignment.

Placebo:A placebo is an inactive pill, liquid, or powder that has no treatment value. Inclinical trials, experimental treatments are often compared with.

Placebo controlled study:A method of investigation of drugs in which an inactive substance (the placebo) is givento one group of participants, while the drug being tested is given to another group. Theresults obtained in the two groups are then compared to see if the investigationaltreatment is more effective in treating the condition.

Placebo effect:A physical or emotional change, occurring after a substance is taken or administered,that is not the result of any special property of the substance. The change may bebeneficial, reflecting the expectations of the participant or the expectations of the person

giving the substance.

Randomization:A method based on chance by which study participants are assigned to a treatmentgroup.Randomization minimizes the differences among groups by. equally distributing peoplewith particular characteristics among all the trial arms.


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The researchers do not know which treatment is better. From what is known at thetime?, any one of the treatments chosen could be of benefit to the participant.

Randomized trial:A study in which participants are randomly (i.e., by chance) assigned to one of two ormore treatment arms of a clinical trial. Occasionally placebos are utilized.

Risk-benefit ratio:The risk to individual participants versus the potential benefits. The risk/benefit ratiomay differ depending on the condition being treated.

Single-blind study:A study in which one party, either the investigator or participant, is unaware of whatmedication the participant is taking; also called single-masked study.

Standard treatment:A treatment currently in wide use and approved by the FDA, considered to be effective inthe treatment of a specific disease or condition.

PHASES OF CLINICAL TRAILS

Trials are in four phases:

1) Phase Itests a new drug or treatment in a small group;2) Phase IIexpands the study to a larger group of people;3) Phase IIIexpands the study to an even larger group of people;4) Phase IVtakes place after the drug or treatment has been licensed and marketed.

1)PHASE-IObjective

To Determine, Metabolic action Pharmacological actions Maximum Tolerated dose

Factors to be Identified are Bioavailability Bioequivalence Dose proportionality Metabolism Pharmacodynamics Pharmacokinetics

Data focus Vital signs Plasma & serum level Adverse events


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Design Features

Single ascennding dose Unblinded

UncontrolPopulation

Healthy volunteers or individual with targeted disease

Duration: 1- Month ( 1.5 years) Sample size: 20-80 Example: Study of a single dose of drug X in normal subjects

2)PHASE-IIObjective

To Evaluate

Effectiveness Determine the short term side effect Identify common risks for a specific population & disease

Factors to be Identified are

Bioavailability Drug-drug interaction Drug-Disease interaction Efficacy at various doses

Pharmacodynamics Pharmacokinetics Patient safety

Data focus

Dose response & Tolerance Adverse events Efficacy

Design Features

Placebo controlled comparison Active controlled comparison Well defined entery criteria

Population

Individual with targeted disease

Duration: 2 Years Sample size: 100-500 Example: Double Blind Study evaluating safety of drug X vs. Placebo in patient


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3)PHASE-IIIObjective

To Obtain Additional information about the effectiveness on clinical outcome Evaluate the overall risk- benefit ratio in a demographically diverse sample

Factors to be Identified

Drug-drug interaction Drug-Disease interaction Dosage intervals Risk-Benefit information Efficacy & Safety for patients

Data focus

Laboratory data Efficacy Adverse events

Design Features

Randomized Controlled 2-3 Treatment arms Broader eligibility criteria

Population

Individual with targeted disease

Duration: 3.5 years Sample size: 1000-5000 Example: Study of Drug X vs. Standard treatment.

4)PHASE-IVObjective

To Monitor

Safety in large populations

Identify additional uses of the agent that might be approved by the FDAFactors to be Identified

Epidemiological data Efficacy & Safety within large diverse population Pharmacoeconomics


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Data focus

Efficacy Pharmacoeconomics

Epidemiology Adverse events

Design Features

Uncontrolled Observational

Population

Individual with targeted disease As well as new age groups & Gender

Duration: Ongoing ( Following FDA approval) Sample size: Several Thousands Example: Study of economic benefit of newly approved Drug X vs. Standardtreatment

TYPES OF CLINICAL TRIALS

i. Treatmentii. Prevention

iii. Screening and early detectioniv. Diagnosticv. Genetics

vi. Quality-of-life / supportive careCLINICAL TRIAL PROTOCOL

A written, detailed action plan that:

Provides background about the trial Specifies trial objectives Describes trials design and organization Ensures that trial procedures are consistently carried out

CLINICAL TRIAL DESIGN Eligibility criteria: Can range from general (age, sex, type of cancer) to specific

(prior treatment, tumor characteristics, blood cell counts, organ function); eligibilitycriteria also vary with trial phaseVaries with protocol and phases

Endpoint: Measurable outcome that indicates an interventions effectiveness.


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Randomization:A method used to prevent bias

in research; a computer or atable of random numbersgenerates treatmentassignments, and participantshave an equal chance to beassigned to one of two or more

groups (e.g., the control groupor the investigational group)

Stratification:Categorizing subjects intosubgroups by specificcharacteristicsEnables researchers to lookinto separate subgroups to seewhether differences exist


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Specific Antidotes

There is a popular misconception that there is an antidote for every poison. Actually,

selective antidotes are available for only a few classes of toxins. The major antidotes andtheir characteristics are listed in Table (Chapter:59, Page:964, KATZUNG )

Examples of Specific Antidotes.

Antidote Poison(s) CommentsAcetylcysteine

(Acetabate,

Mucomyst)

Acetaminophen Best results if given within 810 hours of

overdose. Follow liver function tests and

acetaminophen blood levels. Acetabate is

given intravenously; Mucomyst, orally.

Atropine Anticholinesterases:

organophosphates,carbamates

A test dose of 12 mg (for children, 0.05

mg/kg) is given IV and repeated untilsymptoms of atropinism appear

(tachycardia, dilated pupils, ileus). Dose

may be doubled every 1015 minutes,

with decrease of secretions as

therapeutic end point.

Bicarbonate,

sodium

Membrane-depressant

cardiotoxic drugs

(tricyclic antidepressants,

quinidine, etc)

12 mEq/kg IV bolus usually reverses

cardiotoxic effects (wide QRS,

hypotension). Give cautiously in heart

failure (avoid sodium overload).

Calcium Fluoride; calcium channelblockers

Large doses may be needed in severecalcium channel blocker overdose. Start

with 15 mg/kg IV.

Deferoxamine Iron salts If poisoning is severe, give 15 mg/kg/h

IV. Urine may become pink. 100 mg of

deferoxamine binds 8.5 mg of iron.

Digoxin

antibodies

Digoxin and related

cardiac glycosides

One vial binds 0.5 mg digoxin;

indications include serious arrhythmias,

hyperkalemia.

Esmolol Theophylline, caffeine,metaproterenol

Short-acting blocker reverses 1-induced tachycardia and (possibly) 2-

induced vasodilation. Infuse 2550

mcg/kg/min IV.

Ethanol Methanol, ethylene glycol Ethanol therapy can be started before

laboratory diagnosis is confirmed. A

loading dose is calculated so as to give a


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blood level of at least 100 mg/dL (42

g/70 kg in adults).

Flumazenil Benzodiazepines Adult dose is 0.2 mg IV, repeated as

necessary to a maximum of 3 mg. Do notgive to patients with seizures,

benzodiazepine dependence, or tricyclic

overdose.

Fomepizole Methanol, ethylene glycol More convenient and easier to use than

ethanol. Loading dose 15 mg/kg; repeat

every 12 hours.

Glucagon blockers 510 mg IV bolus may reverse

hypotension and bradycardia that was

resistant to -agonist drugs. May cause

vomiting.

Naloxone Narcotic drugs, other

opioid derivatives

A specific antagonist of opioids; 12 mg

initially by IV, IM, or subcutaneous

injection. Larger doses may be needed to

reverse the effects of overdose with

propoxyphene, codeine, or fentanyl

derivatives. Duration of action (23

hours) may be significantly shorter than

that of the opioid being antagonized.

Oxygen Carbon monoxide Give 100% by high-flow nonrebreathing

mask; use of hyperbaric chamber iscontroversial.

Physostigmine Suggested for

antimuscarinic

anticholinergic agents;

not for tricyclic

antidepressants

Adult dose is 0.51 mg IV slowly. The

effects are transient (3060 minutes),

and the lowest effective dose may be

repeated when symptoms return. May

cause bradycardia, increased bronchial

secretions, seizures. Have atropine ready

to reverse excess effects. Do not use for

tricyclic antidepressant overdose.

Pralidoxime (2-

PAM)

Organophosphate

cholinesterase inhibitors

Adult dose is 1 g IV, which should be

repeated every 34 hours as needed or

preferably as a constant infusion of 250400

mg/h. Pediatric dose is approximately 250

mg. No proved benefit in carbamate

poisoning.

Clinical Trials + Antidotes - Hanouts, By Sir Irfan Hamid

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