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Demystifying Clinical TrialsBridging the Gap From Research to Patient Care
Demystifying Clinical TrialsBridging the Gap From Research to Patient Care
Myra Woolery-Antill, MN, RN
Pediatric Clinical Nurse Specialist
Nursing and Patient Care Services
Warren Grant Magnuson Clinical Center
National Institutes of Health
Barb Biedzycki, MSN, RN, NP
Nurse Practitioner
Sidney Kimmel Comprehensive Cancer Center
at Johns Hopkins
ObjectivesObjectives
! Describe the different phases of clinical trials
! Identify the differences between clinical and research aspects of care including the importance of research assessment, data collection,and documentation
! Discuss implications for patients and families including ethical issues
National Institutes of Health (NIH)National Institutes of Health (NIH)
The Mark O. HatfieldClinical Research Center
Opening December 2004
Warren Grant Magnuson
Clinical Center
Sponsors of Clinical TrialsSponsors of Clinical Trials
!! NIH Sponsored ProgramsNIH Sponsored Programs!! IntramuralIntramural
!!ExtramuralExtramural!! Cooperative groupsCooperative groups
!! Comprehensive cancer centersComprehensive cancer centers
!! Community based research programsCommunity based research programs
!! Pharmaceutical companiesPharmaceutical companies
http://http://clinicaltrialsclinicaltrials..govgov//
What Are Clinical Trials?What Are Clinical Trials?
!Answer a question! Investigate a problem!Determine the efficacy of
an intervention
Clinical research designed to
http://www.cancer.http://www.cancer.govgov//clinicaltrialsclinicaltrials/learning/what/learning/what--isis--aa--clinicalclinical--trialtrial
Types of Clinical TrialsTypes of Clinical Trials
! Preventative! Screening & Early Detection! Diagnostic! Natural History! Therapeutic! Supportive! Genetic and Family
Examples of Clinical TrialsExamples of Clinical Trials
! Prospective! Retrospective! Longitudinal! Cross-sectional! Psychosocial! Behavioral
Obstacles to ConductingClinical TrialsObstacles to ConductingClinical Trials
!! FundingFunding
!! Inadequacies within the science of Inadequacies within the science of clinical trialsclinical trials
!! Inadequate accession of clinical trialsInadequate accession of clinical trials
!! Ethical concernsEthical concerns
!! Professional territorial issuesProfessional territorial issues
Elements of Clinical TrialsElements of Clinical Trials
!High probability of generating useful knowledge
!Benefits
!Selection of subjects
! Informed consent
!Subject’s rights
RisksRisks BenefitsBenefits
RisksRisksBenefitsBenefits RisksRisks
BenefitsBenefits
Protection of Research ParticipantsProtection of Research Participants
http://www.http://www.hhshhs..govgov//ohrpohrp//
http://http://cmecme.cancer..cancer.govgov//clinicaltrialsclinicaltrials/learning//learning/humanparticipanthumanparticipant--protections.aspprotections.asp
Guidelines and Regulations for Clinical ResearchGuidelines and Regulations for Clinical Research
19471947 Nuremberg Code Nuremberg Code (http://(http://ohsrohsr..odod..nihnih..govgov/guidelines//guidelines/nurembergnuremberg.html).html)
19641964 HelsinskiHelsinski DeclarationDeclaration(http://www.(http://www.fdafda..govgov//ococ/health/helsinki89.html)/health/helsinki89.html)
19741974 National Commission for the National Commission for the Protection of Human Subjects of Protection of Human Subjects of Biomedical and Behavioral ResearchBiomedical and Behavioral Research(http://www.(http://www.fasfas..harvardharvard..eduedu/~research/PL93/~research/PL93--348.html)348.html)
19791979 Belmont ReportBelmont Report((http://www.http://www.fdafda..govgov//ococ//ohrtohrt//irbsirbs//belmontbelmont.html).html)
Clinical Trial DevelopmentClinical Trial Development
““ReadyReady,, FireFire, , AimAim!”!”
Clinical Trial PhasesClinical Trial Phases
Phase IPhase I
Phase IIPhase II
Phase IIIPhase III
Phase IVPhase IV
http://www.cancer.http://www.cancer.govgov//clinicaltrialsclinicaltrials/learning/clinical/learning/clinical--trialstrials--educationeducation--seriesseries
Phase I Clinical TrialsPhase I Clinical Trials
! Establish maximum tolerated dose and dosing schedule
! Determine drug pharmacology! Identify side effects & toxicities
Adult Phase I Clinical TrialsAdult Phase I Clinical Trials
! Small dose of drug arbitrarily chosen
! Dose given to 15 - 80 subjects! Toxicity monitored & dose
increased! Continue escalating until side
effects are not tolerable (MTD)
Pediatric Phase I Clinical TrialsPediatric Phase I Clinical Trials
! Single agent! Dose Escalation
! Starting dose usually 50 - 80% of adult MTD
! Dose increased by 20% increments
! Usually pharmacologically guided
Phase II Clinical TrialsPhase II Clinical Trials
! Determine antitumor activity in specific cancers
! Determine effectiveness of drug for particular indication(s)
! Determine intervention effects! Gather additional toxicity
information to determine common short term effects
Phase III Clinical TrialsPhase III Clinical Trials
! Prospectively compare:! Investigational therapy
against standard treatment! New intervention with
standard intervention! Gather additional information
about effectiveness & safety
Phase III Clinical TrialsPhase III Clinical Trials
Stratification may be needed to assure balance
Randomization
Pictures Not Available
Phase IV Clinical TrialsPhase IV Clinical Trials
! Delineates additional information about drug’s risk, benefits, and optional use
! Study of different doses and/or schedules of administration
! Integrate investigative treatment with other treatment modalities
Protocol ComponentsProtocol Components
objectivesBackground & Rationale Inclusion
Criteria
Exlcusion
Criteria
Treatment PlanPatient
Monitoring Criteria
Response Criteria
Statistical Considerations Consent Form
http://http://ctepctep.cancer..cancer.govgov/guidelines/templates.html/guidelines/templates.html
Toxicity CriteriaToxicity Criteria
Toxicity Criteria for Toxicity Criteria for MyelosuppressionMyelosuppression
National Cancer InstituteNational Cancer InstituteToxicityToxicity Grade 0Grade 0 Grade 1Grade 1 Grade 2Grade 2 Grade 3Grade 3 Grade 4Grade 4
WBCWBC > 4000> 4000 3000 3000 -- 39003900 2000 2000 -- 29002900 1000 1000 -- 19001900 < 1000< 1000
NeutrophilsNeutrophils > 2000> 2000 1500 1500 -- 19001900 1000 1000 -- 14001400 500 500 -- 900900 < 500< 500
LymphoctesLymphoctes > 2000> 2000 1500 1500 -- 19001900 1000 1000 -- 14001400 500 500 -- 900900 < 500< 500
InfectionInfection NoneNone MildMild ModerateModerate SevereSevere Life Life threateningthreatening
HemoglobinHemoglobin WNLWNL normal normal -- 10.010.0 8 8 -- 10.010.0 6.5 6.5 -- 7.97.9 < 6.5< 6.5
PlateletsPlatelets WNLWNL normal normal -- 75 K75 K 50 K 50 K -- 74,99974,999 25 K 25 K -- 49.9 K49.9 K < 25,000< 25,000
http://http://ctepctep.cancer..cancer.govgov/reporting//reporting/ctcctc.html.html
Informed ConsentInformed Consent
!! Purpose of study and expected study participation durationPurpose of study and expected study participation duration!! Description of drug, procedures, treatments and interventionsDescription of drug, procedures, treatments and interventions!! Description of foreseeable risks or discomfortsDescription of foreseeable risks or discomforts!! Description of benefits from study (subjects & others)Description of benefits from study (subjects & others)!! Alternative procedures or treatment optionsAlternative procedures or treatment options!! Statement of confidentialityStatement of confidentiality!! Compensation for injuryCompensation for injury!! Names and numbers of persons to contactNames and numbers of persons to contact!! Participation is voluntaryParticipation is voluntary
http://www.http://www.hhshhs..govgov//ohrpohrp//humansubjectshumansubjects/guidance//guidance/icic--nonnon--e.e.htmhtm
http://www.http://www.fdafda..govgov//ococ//ohrtohrt//irbsirbs//informedconsentinformedconsent.html.html
Research Research Nurse Nurse
CoordinatorCoordinator
PatientPatient
InvestigatorInvestigator
Clinical Clinical NurseNurse
Clinical Nurse Role Clinical Nurse Role Clinical Nurse Role
!! AdvocateAdvocate!! EducatorEducator!! LiaisonLiaison!! Patient MonitorPatient Monitor!! Data CollectorData Collector!! CommunicatorCommunicator!! FollowFollow--upup
Nursing Role in Clinical TrialsNursing Role in Clinical Trials
AdvocacyAdvocacy!! Promote open communicationPromote open communication!! Encourage discussionsEncourage discussions!! Ensure adequate information is givenEnsure adequate information is given!! Assist family in defining their goals Assist family in defining their goals
and purpose for participationand purpose for participation!! Assess patient’s understanding of Assess patient’s understanding of
risk vs. benefit risk vs. benefit !! Support familySupport family
Nursing Role in Clinical TrialsNursing Role in Clinical Trials
EducationEducation!! Clinical trialClinical trial
!! Protocol requirementsProtocol requirements
!! Medication administrationMedication administration
!! Side effects and symptom Side effects and symptom managementmanagement
!! SelfSelf--care measurescare measures
!! Resources availableResources available
Nursing Role in Clinical TrialsNursing Role in Clinical Trials
Patient MonitoringPatient Monitoring!! AssessmentAssessment
!! Identification of side effectsIdentification of side effects
!! Response to interventionResponse to intervention
!! Data CollectionData Collection!! Specimen collectionSpecimen collection
!! DocumentationDocumentation
Bridging the GapBridging the Gap
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
!! AssessmentAssessment
!! InterventionsInterventions
!! Laboratory & Diagnostic StudiesLaboratory & Diagnostic Studies
!! Medications Medications
!! Care Conferences Care Conferences
!! TeachingTeaching
!! Coordination of ServicesCoordination of Services
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
AssessmentAssessment
Identifying Toxicities Identifying Toxicities Patient DiaryPatient DiaryPatient Diary
FilgrastimFilgrastim/Research Drug/Research Drug
Name: __________ Dose: _____ Cycle Number: ____ Cycle Start DaName: __________ Dose: _____ Cycle Number: ____ Cycle Start Date: ______ Drug Start Date: _________te: ______ Drug Start Date: _________
FeverFever
HeadachesHeadaches
Muscle achesMuscle aches
Bone or joint painBone or joint pain
SIDE EFFECTSSIDE EFFECTS
Daily temperatureDaily temperature
Indicate reason for missed dose*Indicate reason for missed dose*
Time dose givenTime dose given
DateDate
* If you missed a dose write “M” in the box* If you missed a dose write “M” in the box.
Follow-upFollow-up Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
InterventionsInterventions!! Management and effectivenessManagement and effectiveness
!! Response to therapy or treatmentResponse to therapy or treatment
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
Laboratory and Diagnostic StudiesLaboratory and Diagnostic Studies!! Routine labs and diagnostic studies Routine labs and diagnostic studies
!! Research specimensResearch specimens
!! Blood limitsBlood limits
!! Drug levelsDrug levels
!! Pharmacokinetics and serial blood testsPharmacokinetics and serial blood tests
PharmacokineticsPharmacokineticsPharmacokinetics
Studies performed to determine Studies performed to determine the absorption, distribution, the absorption, distribution, metabolism, and excretion of metabolism, and excretion of investigational agents as well investigational agents as well as their effects on the bodyas their effects on the body
PharmacokineticsPharmacokineticsPharmacokineticsNursing Considerations in
Pharmacokinetics/Serial BloodsNursing Considerations in Nursing Considerations in
Pharmacokinetics/Serial BloodsPharmacokinetics/Serial Bloods
!! IV accessIV access
!! Sampling siteSampling site
!! Medication administrationMedication administration
!! DocumentationDocumentation
!! Sampling timeSampling time
!! Transporting specimensTransporting specimens
PK WorksheetPK WorksheetPK Worksheet
FilgrastimFilgrastim/Research Drug Pharmacokinetic Worksheet/Research Drug Pharmacokinetic Worksheet
Patient Name:______________________ SPatient Name:______________________ Study ID#:_______________tudy ID#:_______________
Height (cm): ________ Weight (kg): __________ Height (cm): ________ Weight (kg): __________ BSA : _____________BSA : _____________
FilgrastimFilgrastim/Research Dose (mcg): _______ Date: _____________ Time : _/Research Dose (mcg): _______ Date: _____________ Time : _____________
6 hr post6 hr post6622
4 hr post4 hr post5511
3 hr post3 hr post4411
2 hr post2 hr post3311
1 hr post1 hr post2211
Pre dosePre dose1111
Central Central
Line or PIVLine or PIV
Actual Actual TimeTimeTime DueTime DueTimeTimeDateDateSample #Sample #DayDay
R115777 Biologic EffectsR115777 Biologic Effects
0
500
1000
1500
2000
2500
3000
3500
4000
Pre Steady State
165 mg/m 2
200 mg/m 2
275 mg/m 2
375 mg/m 2
FTaseActivity
(cpm)
0
500
1000
1500
2000
2500
3000
3500
4000
Pre Steady State
165 mg/m 2
200 mg/m 2
275 mg/m 2
375 mg/m 2
FTaseActivity
(cpm)
Inhibition of Inhibition of FarnesyltransferaseFarnesyltransferase
PK StudiesPK StudiesPK Studies
DrugDrugConcentrationConcentration
TimeTime
Pharmacokinetic SamplingPharmacokinetic SamplingPharmacokinetic Sampling
!!LabelingLabeling
!!TransportationTransportation
!!ProcessingProcessing
!!DocumentationDocumentation
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
MedicationsMedications!! VerificationVerification
!! DocumentationDocumentation
!! Side effectsSide effects
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
Care ConferencesCare Conferences!! Guided by clinical or research aspectsGuided by clinical or research aspects
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
TeachingTeaching!! Disease process and symptom managementDisease process and symptom management
!! MedicationsMedications
!! MonitoringMonitoring
!! Self CareSelf Care
!! NotificationNotification
Comparison of Clinical and Research Aspects of CareComparison of Clinical and Research Aspects of Care
Coordination of ServicesCoordination of Services!! CommunicationCommunication
!! Medication preparation and deliveryMedication preparation and delivery
Case ScenariosCase Scenarios Adult Case StudyAdult Case Study
Ms. T. G. is a semiMs. T. G. is a semi--retired R.N. newly retired R.N. newly diagnosed with stage IV pancreatic cancerdiagnosed with stage IV pancreatic cancer
Eager to join phase II vaccine study because Eager to join phase II vaccine study because she heard it makes a difference and she she heard it makes a difference and she doesn’t want to diedoesn’t want to die
Disease progression ……continues on studyDisease progression ……continues on study
Ethical IssuesEthical Issues
Respect for personsRespect for persons
AutonomyAutonomy
SelfSelf--determination determination
PrivacyPrivacy
National Commission for the Protection of Human Subjects of ReseNational Commission for the Protection of Human Subjects of Research (1979). The arch (1979). The Belmont Report: Ethical Principles and Guidelines for the ProtecBelmont Report: Ethical Principles and Guidelines for the Protection of Human tion of Human Subjects for Research. Available at Subjects for Research. Available at www.www.fdafda..govgov//ococ//ohrtohrt//irbsirbs//belmontbelmont.html.html
Potential Research CandidatePotential Research Candidate
Mrs. D. P.Mrs. D. P.
!! 57 year old widow with 2 adult children57 year old widow with 2 adult children!! Newly diagnosed with multiple myelomaNewly diagnosed with multiple myeloma!! Interested in a phase I vaccine research Interested in a phase I vaccine research
studystudy
The Ethical IssuesThe Ethical Issues
The Belmont ReportThe Belmont Report
!! Respect for personRespect for person!! BeneficenceBeneficence!! JusticeJustice
National Commission for the Protection of Human Subjects of ReseNational Commission for the Protection of Human Subjects of Research arch (1979). The Belmont Report: Ethical Principles and Guidelines fo(1979). The Belmont Report: Ethical Principles and Guidelines for the r the Protection of Human Subjects for Research. Available at Protection of Human Subjects for Research. Available at www.www.fdafda..govgov//ococ//ohrtohrt//irbsirbs//belmontbelmont.html.html
The Next VisitThe Next Visit
Mrs. D. P., her daughter, and 3 grandchildrenMrs. D. P., her daughter, and 3 grandchildren
Illiteracy does not equal incompetence.Illiteracy does not equal incompetence.
Comprehension is relative.Comprehension is relative.
Factors associated with a greater knowledgeFactors associated with a greater knowledge
!! College educationCollege education!! Speak only English at homeSpeak only English at home!! Read consent carefullyRead consent carefully!! Time to considerTime to consider!! Nurse present Nurse present !! Received simplified consentReceived simplified consent
JoffeJoffe, S., Cook, E.F., Cleary, P.D., Clark, J.W., & Weeks, J.C. , S., Cook, E.F., Cleary, P.D., Clark, J.W., & Weeks, J.C. (2001). Lancet Vol.358:1772(2001). Lancet Vol.358:1772––77..
Consent GuidelinesConsent Guidelines
Be clear and concise.Be clear and concise.
Check reading level…Check reading level…
usually 8usually 8thth grade is okay.grade is okay.
Check for understanding frequently.Check for understanding frequently.
Pediatric Case ScenarioPediatric Case Scenario
KaitlynKaitlyn is a preschooler who has refractory stage IV is a preschooler who has refractory stage IV neuroblastoma. She has been referred to your neuroblastoma. She has been referred to your institution for the phase II protocol of institution for the phase II protocol of TemacideTemacide. Her . Her parents have been searching everywhere for treatment parents have been searching everywhere for treatment options and are desperate to be entered into this study. options and are desperate to be entered into this study.
Pediatric Case ScenarioPediatric Case Scenario
Twenty subjects are to be accrued on the Twenty subjects are to be accrued on the TemacideTemacide study. study. KaitlynKaitlyn would be subject #7 if she meets eligibility criteria. would be subject #7 if she meets eligibility criteria.
"" Three of the six patients have died of disease progression Three of the six patients have died of disease progression
"" One patient is experiencing severe complications of the treatmenOne patient is experiencing severe complications of the treatment t regimenregimen
"" The remaining two subjects have stable disease and are The remaining two subjects have stable disease and are experiencing minimal to moderate side effectsexperiencing minimal to moderate side effects
Pediatric Case ScenarioPediatric Case Scenario
!! Based on your knowledge of the research Based on your knowledge of the research findings should the study continue to accrue subjects?findings should the study continue to accrue subjects?
!! How should the findings be shared with the family during How should the findings be shared with the family during the informed consent process if at all?the informed consent process if at all?
!! How will the parents motives for participation influence How will the parents motives for participation influence their decision?their decision?
!! Do you believe this family can give an informed consent Do you believe this family can give an informed consent that is in the best interest of their child?that is in the best interest of their child?
Adolescent Case ScenarioAdolescent Case Scenario
Michael is a 15 year who presents to your clinical setting to ruMichael is a 15 year who presents to your clinical setting to rule le out Sarcoma. out Sarcoma.
He is accompanied by his parents. His family informs you they He is accompanied by his parents. His family informs you they do not want him to know his potential diagnosis.do not want him to know his potential diagnosis.
After completing diagnostic work up, he is eligible for the After completing diagnostic work up, he is eligible for the Sarcoma research protocol. Sarcoma research protocol.
Adolescent Case ScenarioAdolescent Case Scenario
!! Is it acceptable to enter a teenager who does not Is it acceptable to enter a teenager who does not know their diagnosis on a research study?know their diagnosis on a research study?
!! How do you obtain an informed assent or do you?How do you obtain an informed assent or do you?
!! How do you respect the parent’s wishes but maintain How do you respect the parent’s wishes but maintain honesty with Michael?honesty with Michael?
!! What do you do if Michael asks you why the other What do you do if Michael asks you why the other children in the clinical setting are bald?children in the clinical setting are bald?
!! How would you teach him about treatment side How would you teach him about treatment side effects and management?effects and management?
Ethical Issues in PediatricEthical Issues in PediatricEthical Issues in Pediatric
!!Informed consentInformed consent
!!Truth tellingTruth telling
!!Minor assentMinor assent
!!FutilityFutilityhttp://www.http://www.hhshhs..govgov//ohrpohrp/children//children/
http://www.http://www.fdafda..govgov//ococ//ohrtohrt//irbsirbs//informedconsentinformedconsent.html#children.html#children
RisksRisks BenefitsBenefits Slide Not Available
QuestionsQuestions
Slide Not Available