Basics of Clinical Research for humans.p

basic information about clinical research

1. Basics of Clinical Basics of Clinical
ResearchResearch
Beth Elinoff, RN, MPH, CCRCBeth Elinoff, RN, MPH, CCRC
Human Immunology Research CoordinatorHuman Immunology Research Coordinator

2. What is Clinical Research/What is Clinical Research/
Human Subject Research?Human Subject Research?
Department of Health and Human Services Department of Health and Human Services
(DHHS) Definitions (45 CFR 46.102):(DHHS) Definitions (45 CFR 46.102):

1. Human Subject Research1. Human Subject Research
In order for activities to be deemed “Human Subject In order for activities to be deemed “Human Subject
Research” by the DHHS, they must meet the definition Research” by the DHHS, they must meet the definition
of “research” and involve one or more “human of “research” and involve one or more “human
subjects” as defined by DHHS regulations.subjects” as defined by DHHS regulations.

3. DHHS Definitions (con’t)DHHS Definitions (con’t)

A. ResearchA. Research
““A systematic investigation, including research A systematic investigation, including research
development, testing and evaluation, designed to development, testing and evaluation, designed to
develop or contribute to generalizable knowledge.”develop or contribute to generalizable knowledge.”

Belmont Report Definition of ResearchBelmont Report Definition of Research
““Any activity designed to test a hypothesis, permit Any activity designed to test a hypothesis, permit
conclusions to be drawn and thereby to develop or conclusions to be drawn and thereby to develop or
contribute to generalizable knowledge (expressed, for contribute to generalizable knowledge (expressed, for
example, in theories, principles, and statements of example, in theories, principles, and statements of
relationships).”relationships).”

4. DHHS Definitions (con’t)DHHS Definitions (con’t)

B. Human Subjects:B. Human Subjects:
““A living individual about whom an investigator A living individual about whom an investigator
conducting research obtains (1) data through conducting research obtains (1) data through
intervention or interaction with the individual; or (2) intervention or interaction with the individual; or (2)
identifiable private information.”identifiable private information.”

5. DHHS Definitions (con’t)DHHS Definitions (con’t)

Intervention:Intervention:
Includes both the physical procedures by which data Includes both the physical procedures by which data
are gathered (eg. blood draw) and manipulations of the are gathered (eg. blood draw) and manipulations of the
subject or the subject’s environment that are performed subject or the subject’s environment that are performed
for research purposes for research purposes

Interaction:Interaction:
Includes communication or interpersonal contact (eg. Includes communication or interpersonal contact (eg.
questionnaires, interviews) between the investigator and questionnaires, interviews) between the investigator and
subjectsubject

6. DHHS Definitions (con’t)DHHS Definitions (con’t)

Private Information:Private Information:
Includes information about behavior that occurs in a Includes information about behavior that occurs in a
context in which an individual can reasonably expect context in which an individual can reasonably expect
that no observation or recording is taking place, and that no observation or recording is taking place, and
information which has been provided for specific information which has been provided for specific
purposes by an individual and which the individual can purposes by an individual and which the individual can
reasonably expect will not be made public (eg. medical reasonably expect will not be made public (eg. medical
record). Private information must be individually record). Private information must be individually
identifiable (eg. the identity of the subject is or may identifiable (eg. the identity of the subject is or may
readily be ascertained by the investigator or associated readily be ascertained by the investigator or associated
with the information).with the information).

7. Food and Drug Administration Food and Drug Administration
(FDA) Definition of Human Subject (FDA) Definition of Human Subject
ResearchResearch

FDA has different definitions of “research” and FDA has different definitions of “research” and
“human subjects”“human subjects”

FDA guidelines must be followed when using a FDA guidelines must be followed when using a
drug or device in the studydrug or device in the study

8. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
1.1.Public Health Service Syphilis Study ’32-’71Public Health Service Syphilis Study ’32-’71

Better known as the “Tuskeegee Syphilis Study”Better known as the “Tuskeegee Syphilis Study”

Originally designed to make treatment available to Originally designed to make treatment available to
African-American men with syphilis, even though there African-American men with syphilis, even though there
was no known effective treatmentwas no known effective treatment

Issues:Issues:
1.1.Men were recruited without their consentMen were recruited without their consent
2.2.Misinformation about procedures, ie spinal tapsMisinformation about procedures, ie spinal taps
3.3.After penicillin was proven an effective treatment ’40’s), men After penicillin was proven an effective treatment ’40’s), men
were denied antibiotics and prevented treatment from military were denied antibiotics and prevented treatment from military
and local physiciansand local physicians

9. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
2.2.US Food, Drug and Safety Act (1938)US Food, Drug and Safety Act (1938)

107 people died after taking sulfanilamide, a cold 107 people died after taking sulfanilamide, a cold
remedy that contained anti-freeze. remedy that contained anti-freeze.

This act enforces manufacturers to demonstrate This act enforces manufacturers to demonstrate
drug safety.drug safety.

10. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
3.3.Nuremberg Code (1947)Nuremberg Code (1947)

Result of the trial of Nazi doctors and scientists from Result of the trial of Nazi doctors and scientists from
WWII – no guidelines for human researchWWII – no guidelines for human research

Guidelines:Guidelines:
1.1.Need for informed consentNeed for informed consent
2.2.Research should be based on prior animal workResearch should be based on prior animal work
3.3.Risks should be justified by anticipated benefitsRisks should be justified by anticipated benefits
4.4.Only qualified scientists must conduct researchOnly qualified scientists must conduct research
5.5.Physical and mental suffering must be avoidedPhysical and mental suffering must be avoided
6.6.No research where death/severe injury is expectedNo research where death/severe injury is expected

11. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
3.3.Nuremberg Code (con’t)Nuremberg Code (con’t)

Problems:Problems:
1.1.Little impact on research done in the US – thought to Little impact on research done in the US – thought to
condemn Naziscondemn Nazis
2.2.No strength of the law behind itNo strength of the law behind it
3.3.Only applied to non-therapeutic human subject researchOnly applied to non-therapeutic human subject research

12. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
4.4.Declaration of Helsinki (1964)Declaration of Helsinki (1964)

Code of ethics developed by the World Medical Code of ethics developed by the World Medical
Association (now known and World Health Org)Association (now known and World Health Org)

Broader than Nuremberg CodeBroader than Nuremberg Code

Geared towards therapeutic medical researchGeared towards therapeutic medical research

Recommended informed consentRecommended informed consent

Precursor to IRB requirementPrecursor to IRB requirement

Journals required all published research to follow Journals required all published research to follow
Declaration’s guidelinesDeclaration’s guidelines

13. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
5.5.The National Research Act (1974)The National Research Act (1974)

Culmination of hearings by US Congress Culmination of hearings by US Congress
established the National Commission for the established the National Commission for the
Protection of Human Subjects of Biomedical and Protection of Human Subjects of Biomedical and
Behavioral ResearchBehavioral Research

Purpose of The National Commission:Purpose of The National Commission:
1.1.Identify basic ethical principles underlying the Identify basic ethical principles underlying the
conduct of human subject researchconduct of human subject research
2.2.Develop guidelines to ensure conduct of human Develop guidelines to ensure conduct of human
subject research in accordance with those principlessubject research in accordance with those principles

14. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
5.5.The National Research Act (con’t)The National Research Act (con’t)

45 CFR 46 – “Regulations for the Protection of 45 CFR 46 – “Regulations for the Protection of
Human Subjects of Biomedical and Behavioral Human Subjects of Biomedical and Behavioral
Research”; Issued by the Department of Health, Research”; Issued by the Department of Health,
Education and Welfare (later renamed DHHS)Education and Welfare (later renamed DHHS)

Revisions made in late 1970’s and early 1980’sRevisions made in late 1970’s and early 1980’s

By 1991, 16 other federal agencies/departments By 1991, 16 other federal agencies/departments
applied 45 CFR 46 to research they fund/conductapplied 45 CFR 46 to research they fund/conduct

Referred to as the “Common Rule”Referred to as the “Common Rule”

15. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
6.6.The Belmont Report (1979)The Belmont Report (1979)

Issued by the National Commission for the Issued by the National Commission for the
Protection of Human Subjects of Biomedical and Protection of Human Subjects of Biomedical and
Behavioral ResearchBehavioral Research

Purpose: resolve ethical problems that surround Purpose: resolve ethical problems that surround
the conduct of human subject researchthe conduct of human subject research

One principle does not outweigh another; each has One principle does not outweigh another; each has
equal weightequal weight

16. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
6.6.The Belmont Report (con’t)The Belmont Report (con’t)
The three principles:The three principles:
1.1.Respect for Persons – treat people as autonomous Respect for Persons – treat people as autonomous
creatures and not a means to an end; provide extra creatures and not a means to an end; provide extra
protection for those with limited autonomy protection for those with limited autonomy

Requires informed consentRequires informed consent

Requires respect of privacy of research subjectsRequires respect of privacy of research subjects

17. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
6.6.The Belmont Report (con’t)The Belmont Report (con’t)
The three principles:The three principles:
2.2.Beneficence – minimize harm and maximize Beneficence – minimize harm and maximize
benefitbenefit

Requires use of the best possible research design to Requires use of the best possible research design to
maximize benefit and minimize harmmaximize benefit and minimize harm

Requires researchers to be able to perform the Requires researchers to be able to perform the
procedures and manage the risksprocedures and manage the risks

Prohibits research without a favorable risk-benefit ratioProhibits research without a favorable risk-benefit ratio

18. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
6.6.The Belmont Report (con’t)The Belmont Report (con’t)
The three principles:The three principles:
3.3.Justice – treat all people fairly and ensure burdens Justice – treat all people fairly and ensure burdens
and benefits are shared equitablyand benefits are shared equitably

Requires equitable selection of research subjectsRequires equitable selection of research subjects

Requires avoidance of exploitation of vulnerable Requires avoidance of exploitation of vulnerable
populations or populations of convenience (ie pregnant populations or populations of convenience (ie pregnant
women; children; incarcerated populations)women; children; incarcerated populations)

19. History of Development of Human History of Development of Human
Research ProtectionsResearch Protections
7.7.International Conference on Harmonisation - International Conference on Harmonisation -
ICH (1990)ICH (1990)

Joint regulatory/industry project to improve Joint regulatory/industry project to improve
process of developing new products between process of developing new products between
Japan, Europe and United StatesJapan, Europe and United States

Allows for international research studies to follow Allows for international research studies to follow
same rules/regulationssame rules/regulations

Conference convenes to update regulationsConference convenes to update regulations

Established “Good Clinical Practices” Established “Good Clinical Practices”

20. Good Clinical PracticesGood Clinical Practices

Known as GCP’sKnown as GCP’s

Misnomer – they are rules/regulations for the Misnomer – they are rules/regulations for the
conduct of researchconduct of research

Sometimes called “Good Research Practices”Sometimes called “Good Research Practices”

Standard for the design, conduct, performance, Standard for the design, conduct, performance,
monitoring, analyses and reporting of research monitoring, analyses and reporting of research

Even though established for drug studies, they Even though established for drug studies, they
dictate appropriate conduct for all researchdictate appropriate conduct for all research

21. Innovative Practice vs. ResearchInnovative Practice vs. Research

Innovative clinical practice is an intervention designed Innovative clinical practice is an intervention designed
solely to enhance the well-being of an individual patient solely to enhance the well-being of an individual patient
or client. The purpose is to provide diagnosis, or client. The purpose is to provide diagnosis,
preventative treatment, or therapy to particular preventative treatment, or therapy to particular
individuals.individuals.

Considered “research” only if previous criteria is met.Considered “research” only if previous criteria is met.

At UPMC, the introduction of innovative procedures At UPMC, the introduction of innovative procedures
or therapies into clinical practice (when research is not or therapies into clinical practice (when research is not
involved), requires review by department chair and the involved), requires review by department chair and the
UPMC Technology Assessment Committee/Innovative UPMC Technology Assessment Committee/Innovative
Practices Sub-Committee prior to implementation.Practices Sub-Committee prior to implementation.

22. Quality Assurance vs. ResearchQuality Assurance vs. Research

Precise definitions to permit the distinction between Precise definitions to permit the distinction between
research studies and quality assurance projects are research studies and quality assurance projects are
difficult and have not been established. In general, a difficult and have not been established. In general, a
quality assurance project is a project that is focused quality assurance project is a project that is focused
primarily on improving patient care within a given primarily on improving patient care within a given
patient care environment and, as such, the outcome patient care environment and, as such, the outcome
may not be generalizable to other patient care may not be generalizable to other patient care
environments.environments.

Both UPMC and CHP require the submission of all Both UPMC and CHP require the submission of all
quality assurance projects for review.quality assurance projects for review.

23. Questions to distinguish QA from ResearchQuestions to distinguish QA from Research
(any yes response indicates research)(any yes response indicates research)
1.1.Is there a commitment, in advance of data collection, to a Is there a commitment, in advance of data collection, to a
corrective plan given any one of a number of study outcomes? corrective plan given any one of a number of study outcomes?
Does the PI of the study have both clinical supervisory Does the PI of the study have both clinical supervisory
responsibility and the authority to impose change?responsibility and the authority to impose change?
2.2.Is the research being sponsored/funded by an external agency?Is the research being sponsored/funded by an external agency?
3.3.Does the proposed study involve the prospective assignment Does the proposed study involve the prospective assignment
of patients to different procedures or therapies based on a of patients to different procedures or therapies based on a
predetermined plan?predetermined plan?
4.4.Does the proposed study involve a “control group” in whom Does the proposed study involve a “control group” in whom
the therapeutic or study intervention is intentionally withheld the therapeutic or study intervention is intentionally withheld
to allow an assessment of its efficacy?to allow an assessment of its efficacy?

24. Questions to distinguish QA from ResearchQuestions to distinguish QA from Research
5.5.Will the study intervention be delivered in a blinded fashion Will the study intervention be delivered in a blinded fashion
wherein neither the physician nor the patient knows to whom the wherein neither the physician nor the patient knows to whom the
study intervention or comparative intervention (eg. standard care, study intervention or comparative intervention (eg. standard care,
placebo) was given?placebo) was given?
6.6.Is the assessment of outcome blinded to the study intervention Is the assessment of outcome blinded to the study intervention
for purpose of establishing the efficacy of the intervention?for purpose of establishing the efficacy of the intervention?
7.7.Does the proposed study involve the prospective evaluation of a Does the proposed study involve the prospective evaluation of a
drug, biologic or device that is not currently approved for general drug, biologic or device that is not currently approved for general
use by the FDA?use by the FDA?
8.8.Will patients involved in the proposed study be exposed to Will patients involved in the proposed study be exposed to
additional risks or burdens beyond standard clinical practice in additional risks or burdens beyond standard clinical practice in
order to make the results of the study generalizable?order to make the results of the study generalizable?

25. Types of Study DesignsTypes of Study Designs
1.1.Observational DesignsObservational Designs

26. Types of Observational StudiesTypes of Observational Studies

Cohort StudiesCohort Studies

A group of subjects followed over timeA group of subjects followed over time

Purpose: defining the incidence and investigating Purpose: defining the incidence and investigating
potential causes of a condition (incidence)potential causes of a condition (incidence)

Can be prospective – investigator chooses a sample Can be prospective – investigator chooses a sample
group and measures characteristics in each subject group and measures characteristics in each subject
over a period of time that might predict outcomesover a period of time that might predict outcomes

Can be retrospective – same as prospective, except Can be retrospective – same as prospective, except
all data collection and follow-up has happened in the all data collection and follow-up has happened in the
past; only possible if adequate data is availablepast; only possible if adequate data is available

27. Types of Observational StudiesTypes of Observational Studies

Cross-Sectional StudiesCross-Sectional Studies

Similar to cohort studies except all the Similar to cohort studies except all the
measurements are made at one time point with no measurements are made at one time point with no
follow-upfollow-up

Purpose: describing variables and their distribution Purpose: describing variables and their distribution
patterns (prevalence)patterns (prevalence)

Strength – fast and inexpensive since there is no Strength – fast and inexpensive since there is no
follow-up or waiting time for outcomefollow-up or waiting time for outcome

28. Types of Observational StudiesTypes of Observational Studies

Case-Control StudiesCase-Control Studies

Two groups of people examined for the same Two groups of people examined for the same
outcomeoutcome

Group 1 – “cases” or a population of people with a Group 1 – “cases” or a population of people with a
certain diseasecertain disease

Group 2 – “controls” or a population of people without Group 2 – “controls” or a population of people without
that same disease that same disease

Purpose: compare prevalence of risk factor(s) in Purpose: compare prevalence of risk factor(s) in
subjects with the disease (cases) versus subjects subjects with the disease (cases) versus subjects
without the disease (controls) without the disease (controls)

29. Types of Study DesignsTypes of Study Designs
1.1.Observational DesignsObservational Designs
1.1.Experimental Designs – Experimental Designs – interventional interventional
studiesstudies

30. Experimental StudiesExperimental Studies

These studies evaluate the effects of an These studies evaluate the effects of an
interventionintervention

Types of interventions:Types of interventions:

Behavior modification (eg. a walking program to improve Behavior modification (eg. a walking program to improve
weight loss)weight loss)

Drug (eg. a new investigational drug or studying a drug Drug (eg. a new investigational drug or studying a drug
for off-label use – subject to FDA regulations)for off-label use – subject to FDA regulations)

Device (eg. a new investigational stent – subject to FDA Device (eg. a new investigational stent – subject to FDA
regulations)regulations)

Strength: Can demonstrate causalityStrength: Can demonstrate causality

31. Phases of Experimental StudiesPhases of Experimental Studies

Phase I:Phase I:
Unblinded studies of a small number of healthy Unblinded studies of a small number of healthy
volunteers to test safety of treatment (can sometimes volunteers to test safety of treatment (can sometimes
use people with the disease)use people with the disease)

Phase II:Phase II:
Randomized studies of relatively small number of Randomized studies of relatively small number of
people with the disease to test dose ranges and/or people with the disease to test dose ranges and/or
efficacy of treatment efficacy of treatment

32. Phases of Experimental StudiesPhases of Experimental Studies

Phase III:Phase III:
Randomized studies of large number of people with Randomized studies of large number of people with
the disease to test efficacy of treatment on pre-the disease to test efficacy of treatment on pre-
selected outcomesselected outcomes

Phase IV:Phase IV:
Large experimental studies or observational studies Large experimental studies or observational studies
conducted after treatment has been approved by the conducted after treatment has been approved by the
FDA to assess performance of treatment (called FDA to assess performance of treatment (called
Post-Market Studies)Post-Market Studies)

33. Do I really want to Do I really want to
conduct clinical conduct clinical
research?research?

34. What Help is Available?What Help is Available?

University of Pittsburgh IRB/RCCOUniversity of Pittsburgh IRB/RCCO

IRB Coordinators – wealth of knowledge; will IRB Coordinators – wealth of knowledge; will
perform an informal review prior to official reviewperform an informal review prior to official review
www.irb.pitt.edu – IRB manual; required forms; link – IRB manual; required forms; link
to research training website; etc.to research training website; etc.

Sponsored educational activities – monthly “Ask the Sponsored educational activities – monthly “Ask the
IRB” sessions; conferences on current issues; etc.IRB” sessions; conferences on current issues; etc.

Human Immunology Research OfficeHuman Immunology Research Office

35. Human Immunology Human Immunology
Research OfficeResearch Office

Assistance with investigational human studies Assistance with investigational human studies
involving transplantation that are initiated by involving transplantation that are initiated by
STI research or involves substantial support STI research or involves substantial support
from STI researchfrom STI research

Act as repository for all documents related to Act as repository for all documents related to
above studies and all other studies requiring above studies and all other studies requiring
STI research participation (eg. Processing of STI research participation (eg. Processing of
blood samples on 15blood samples on 15
thth
floor BST floor BST

36. Human Immunology Human Immunology
Research OfficeResearch Office

Services Available:Services Available:
1.1.Consultation regarding clinical aspects/logistics of Consultation regarding clinical aspects/logistics of
new projectsnew projects
2.2.IRB summary protocol and consent form IRB summary protocol and consent form
preparation assistancepreparation assistance
3.3.Project coordination:Project coordination:

Assist with recruitment based on projectAssist with recruitment based on project

Ensure proper handling of samples/specimens from Ensure proper handling of samples/specimens from
patient to labpatient to lab

37. Human Immunology Human Immunology
Research OfficeResearch Office

Information to be stored in this office:Information to be stored in this office:
1.1.Copies of all current and future IRB submissionsCopies of all current and future IRB submissions
2.2.Correspondence between IRB and investigators Correspondence between IRB and investigators
including approval letters, audit reports, etcincluding approval letters, audit reports, etc
3.3.Correspondence between sponsor and Correspondence between sponsor and
investigators regarding protocol issuesinvestigators regarding protocol issues
4.4.RPF training certificatesRPF training certificates
5.5.Copies of current CV’sCopies of current CV’s
6.6.Copies of current licensesCopies of current licenses

38. Human Immunology Human Immunology
Research OfficeResearch Office

To request assistance:To request assistance:
1.1.Contact office to set up meeting to discuss project, Contact office to set up meeting to discuss project,
assistance requested, etcassistance requested, etc
2.2.Complete research outline (template will be supplied Complete research outline (template will be supplied
by the office)by the office)

Contact information:Contact information:
Location: E1540 BSTLocation: E1540 BST
Phone: [phone]Phone: [phone]
Email: [email protected]: [email protected]

39. Requirements Prior to IRB Requirements Prior to IRB
SubmissionSubmission

Possible UPMC fiscal approvalPossible UPMC fiscal approval

STI PRC (protocol review committee) approval STI PRC (protocol review committee) approval

Any protocol submitted to the IRB requires prior Any protocol submitted to the IRB requires prior
scientific review; PRC review includes scientific scientific review; PRC review includes scientific
review.review.

submission is reviewed both by an investigator and a submission is reviewed both by an investigator and a
research coordinatorresearch coordinator

Facilitator of committee is Agnes Zachoszcz (all Facilitator of committee is Agnes Zachoszcz (all
submissions are emailed to her)submissions are emailed to her)