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