clinical trials and using games to understand them
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Clinical TrialsClinical Trialsandand
Using Games to Using Games to Understand ThemUnderstand Them
Mary Jane Kurtz and Patrick RafterMary Jane Kurtz and Patrick RafterMinuteman Regional High SchoolMinuteman Regional High School
Bioman Conference July 2007Bioman Conference July 2007Portsmouth, NHPortsmouth, NH
ObjectivesObjectives
To be informed about the process of To be informed about the process of clinical trialsclinical trials
Understand the FDA regulations Understand the FDA regulations guiding the processguiding the process
Prepare a clinical trials game for Prepare a clinical trials game for students to play students to play
FDA.gov/cder/handbook/FDA.gov/cder/handbook/develop.develop.
htmhtm
Five Basic Components of Five Basic Components of Clinical Trials for Clinical Trials for
Investigational New DrugInvestigational New Drug Pre-clinical trials: Animals or Tissue Culture Pre-clinical trials: Animals or Tissue Culture Phase 1 clinical studies: Small, healthy groupsPhase 1 clinical studies: Small, healthy groups Phase 2 clinical studies: Larger, sick Phase 2 clinical studies: Larger, sick
populationpopulation Phase 3 clinical studies: Broad trial with a Phase 3 clinical studies: Broad trial with a
largelarge sick populationsick population
Phase 4 clinical studies: Retrospective look at Phase 4 clinical studies: Retrospective look at drug drug
after released to patientsafter released to patients
What do you know about What do you know about Clinical Trials ? Clinical Trials ?
a) vocabulary: a) vocabulary:
GMP, FDA, IND, CDER, NIH, NDAGMP, FDA, IND, CDER, NIH, NDA b) do you know anyone who went b) do you know anyone who went
through a through a
clinical trial?clinical trial? c) FDA : covers food, drugs, biological c) FDA : covers food, drugs, biological
products, medical processes, products, medical processes, cosmeticscosmetics
What Would You Like to What Would You Like to Find Out ?Find Out ?
How is a clinical trial carried out?How is a clinical trial carried out?
Who is responsible for conducting Who is responsible for conducting these trials ?these trials ?
Drugs must be effective/safeDrugs must be effective/safe
Foreign drugs?Foreign drugs?
History of FDA and CDERHistory of FDA and CDER
FDA established in 1906 with pure food FDA established in 1906 with pure food and and
drug actdrug act
- list ingredients in medicine- list ingredients in medicine
- examine samples for adulterated - examine samples for adulterated food and food and
drugsdrugs
- federal control via interstate - federal control via interstate commercecommerce
Brain Centers
Glands Wear Out!
Epilepsy Treatme
nt
Throat and Lung
Consumption
Remedy
Certificate of
Purity
Energizing Tonic
Lose Weight
Snake Oil
Germ Killer
Renovator
Heart Remedy
Pre-1906 Sales of Medicines
fda/gov/cder/about/history/time.1htm
1938 Food and Drug Act1938 Food and Drug Act
New drugs must be shown to be safe New drugs must be shown to be safe before selling Government controls before selling Government controls marketingmarketing
Includes cosmetics and therapeutic Includes cosmetics and therapeutic devicesdevices
Toxicity information given with drugsToxicity information given with drugs Need for prescriptionsNeed for prescriptions Must be shown Must be shown False and FraudulentFalse and Fraudulent
CDER TimelineCDER Timeline
1906 Food and Drug Act 1906 Food and Drug Act
1953: Factory Inspection; manufacturers must provide 1953: Factory Inspection; manufacturers must provide information about analysis of samplesinformation about analysis of samples
1938 Food, Drug, and Cosmetic Act1938 Food, Drug, and Cosmetic Act
1962: Thalidomide causes widespread birth defects in other 1962: Thalidomide causes widespread birth defects in other countries. Congress institutes supervision over drug safetycountries. Congress institutes supervision over drug safety
1968 : Drug trafficking is now under the control of the 1968 : Drug trafficking is now under the control of the treasury’streasury’s
department of narcotics and dangerous drugsdepartment of narcotics and dangerous drugs
Elixir SulfanilamideElixir Sulfanilamide
Previous Law did not address safety of Previous Law did not address safety of drugsdrugs
This drug was dissolved in diethylene This drug was dissolved in diethylene glycolglycol
Over 100 people died, mostly childrenOver 100 people died, mostly children
Led to a demand for redefining FDA lawsLed to a demand for redefining FDA laws
1938 Food, Drug & 1938 Food, Drug & Cosmetic ActCosmetic Act
Drugs must be tested for safety before Drugs must be tested for safety before being marketedbeing marketed
Drug maker must submit a New Drug Drug maker must submit a New Drug application to obtain approval to sell application to obtain approval to sell drugdrug
This application must include results This application must include results of of
safety regulationssafety regulations Drugs must have adequate labelingDrugs must have adequate labeling
FDA in the 1940’s FDA in the 1940’s
Insulin amendment act: all batches must beInsulin amendment act: all batches must be tested for purity, strength, quality and tested for purity, strength, quality and
identityidentity
Penicillin must be assigned a strength and Penicillin must be assigned a strength and assessment of purityassessment of purity
FDA in the 1950’sFDA in the 1950’s
Adverse reaction reported to Adverse reaction reported to ChloromycetinChloromycetin Dycrasia, bleeding, lack of platelets, and Dycrasia, bleeding, lack of platelets, and
white blood cellswhite blood cells Voluntary drug adverse effects reporting Voluntary drug adverse effects reporting
to FDAto FDA
Big expansion of the FDA to Include 7 Big expansion of the FDA to Include 7
different divisionsdifferent divisions
The Thalidomide StoryThe Thalidomide Story
Drug approved for sleep and nausea Drug approved for sleep and nausea in in
Europe and CanadaEurope and Canada Dr. Francis Kelsey was awarded Dr. Francis Kelsey was awarded
medal of honormedal of honor Was submitted to the FDA but not Was submitted to the FDA but not
approved as a new drug applicationapproved as a new drug application Insufficient safety dataInsufficient safety data Was not approved for marketingWas not approved for marketing
1962 Drug Amendments1962 Drug Amendments
Drugs must both be safe and Drugs must both be safe and effective prior toeffective prior to
being distributedbeing distributed
Antibiotics must be certifiedAntibiotics must be certified
FDA was given control over FDA was given control over marketing of drugsmarketing of drugs
Popular Influence on FDA Popular Influence on FDA ProceduresProcedures
Coalition of activists for Aids cure was Coalition of activists for Aids cure was formed formed
Sought to expand and expedite new Sought to expand and expedite new treatmentstreatments
Orphan drug act institutedOrphan drug act instituted
Anti-tampering act Anti-tampering act
Further Expansion of FDAFurther Expansion of FDA19871987
Center for Drugs /Biologics was split Center for Drugs /Biologics was split intointo
Two Separate UnitsTwo Separate Units
Center for Drug Evaluattion and Research
Center for Biologic sEvaluation and Research
Hatch/Waxman Hatch/Waxman AmendmentsAmendments
19841984 50% of all prescription drugs are generic/cost50$ 50% of all prescription drugs are generic/cost50$
less per prescription than name brandless per prescription than name brand
2000 : 44% of drugs are filled with generic 2000 : 44% of drugs are filled with generic varietiiesvarietiies
Generic drug makers can rely on previous safety Generic drug makers can rely on previous safety & efficacious findings of original drug application& efficacious findings of original drug application
Same application as for NDA but is amendedSame application as for NDA but is amended NDANDA
Pre-Clinical TrialsPre-Clinical Trials Based on fundamental scientific findings Based on fundamental scientific findings
Consists of short-term testing in animals Consists of short-term testing in animals using the compound of interestusing the compound of interest
Usually takes from 2 weeks to 3 monthsUsually takes from 2 weeks to 3 months
Tests toxicity, absorption, clearance of Tests toxicity, absorption, clearance of drugdrug
compound must be biologically safe for compound must be biologically safe for initial administration to humansinitial administration to humans
Clinical TrialsClinical Trials
Pre-Investigational New Drug (IND) Pre-Investigational New Drug (IND) applicationapplication
Two types: observational, interventionalTwo types: observational, interventional Discussion begins about testing phasesDiscussion begins about testing phases
Including data requirementsIncluding data requirements Scientific issuesScientific issues
Required for further testing:Required for further testing: Compound must be biologically activeCompound must be biologically active Compound must be safe for data shownCompound must be safe for data shown
What Drugs Make it to What Drugs Make it to Clinical Trials?Clinical Trials?
Synthesis and PurificationSynthesis and Purification 1/1000 are successful1/1000 are successful 8 ½ years to go through trials8 ½ years to go through trials Drug selection is made by using test models Drug selection is made by using test models
for a disease/adding drug to determine its for a disease/adding drug to determine its effecteffect
Selection by screening – Selection by screening – microorganisms/plantsmicroorganisms/plants
Other forces, price, marketing etc.Other forces, price, marketing etc.
Institutional Review Boards Institutional Review Boards (IRB)(IRB)
Ensures rights for people Ensures rights for people participationparticipation
Must be fully informedMust be fully informed Written consentWritten consent Consists of 5 experts + lay peopleConsists of 5 experts + lay people Must understand specific drug Must understand specific drug
action, law, constitutional action, law, constitutional involvementinvolvement
Phase 1 Clinical Studies Phase 1 Clinical Studies of INDof IND
Drugs used in humansDrugs used in humans Subjects are usually healthy volunteersSubjects are usually healthy volunteers Double blind studiesDouble blind studies Is subject to a clinical hold, 483 issuedIs subject to a clinical hold, 483 issued Monitors the following:Monitors the following:
ToxicityToxicity Drug metabolismDrug metabolism Mechanism of action Mechanism of action
Phase 2 Clinical Studies Phase 2 Clinical Studies of INDof IND
Obtain preliminary data about Obtain preliminary data about effectiveness of the drugeffectiveness of the drug
Determines the common short term side Determines the common short term side effectseffects Risks associated with drugRisks associated with drug
Well controlled, closely monitored Well controlled, closely monitored Usually 100 hundred carefully selected Usually 100 hundred carefully selected
peoplepeople
Controlled TrialsControlled Trials Designed to permit valid comparisons with Designed to permit valid comparisons with
a placebo a placebo Dose response curve is createdDose response curve is created Control is concurrent with tested Control is concurrent with tested
substancesubstance Comparison can be made is earlier studiesComparison can be made is earlier studies Sometimes there is no control: Requires Sometimes there is no control: Requires
special approachspecial approach Multiple resistant pathogens Multiple resistant pathogens
Example extremely drug resistant TB (XDR TB)Example extremely drug resistant TB (XDR TB)
Phase 3 Clinical TrialsPhase 3 Clinical Trials Expanded controlled/uncontrolled trialsExpanded controlled/uncontrolled trials
Measures effectiveness and safety of Measures effectiveness and safety of drugdrug
Includes hundreds-thousands of patientsIncludes hundreds-thousands of patients
Evaluates risk/benefit for majority of Evaluates risk/benefit for majority of peoplepeople Requires statistical analysisRequires statistical analysis
Phase 4 Clinical TrialPhase 4 Clinical Trial
A retrospective view of overall A retrospective view of overall effects of drug on a large population effects of drug on a large population over timeover time
Statistical analysis of effects of Statistical analysis of effects of preventative or palliative drugs on preventative or palliative drugs on overall health of individualoverall health of individual Example : Framingham Nurses Health Example : Framingham Nurses Health
StudyStudy
Women’s Health InitiativeWomen’s Health Initiative15 year analysis of 161,000 15 year analysis of 161,000
womenwomen50-79 years of age50-79 years of age
BenefitsBenefits 57% reduction in 57% reduction in
colon cancercolon cancer Better bone densityBetter bone density Relieves symptoms Relieves symptoms
of menopauseof menopause Improves HDL Improves HDL
cholesterol levelscholesterol levels
RisksRisks 24% increase in 24% increase in
breast cancerbreast cancer 24% increase in 24% increase in
heart disease (stroke, heart disease (stroke, clots)clots)
Increased level of Increased level of dementiadementia
Statistically Statistically insignificantinsignificant
increase in heart increase in heart attacksattacks
http://www.whi.org/findings/ht/eplusp_pad.php
Epidemiologic StudiesEpidemiologic Studies
Unknown factors might be driving Unknown factors might be driving resultsresults
(statistics can be misleading)(statistics can be misleading)
Is not as significant as a blind study Is not as significant as a blind study with controlled groupswith controlled groups
Contradicts other evidence about heart Contradicts other evidence about heart diseasedisease
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