Basics of Clinical Research

Basics of Clinical Basics of Clinical ResearchResearch

Beth Elinoff, RN, MPH, CCRCBeth Elinoff, RN, MPH, CCRC

Human Immunology Research Human Immunology Research CoordinatorCoordinator

What is Clinical Research/What is Clinical Research/Human Subject Research?Human Subject Research?Department of Health and Human Department of Health and Human

Services (DHHS) Definitions (45 Services (DHHS) Definitions (45 CFR 46.102):CFR 46.102):

1. Human Subject Research1. Human Subject ResearchIn order for activities to be deemed “Human In order for activities to be deemed “Human Subject Research” by the DHHS, they must Subject Research” by the DHHS, they must meet the definition of “research” and involve meet the definition of “research” and involve one or more “human subjects” as defined by one or more “human subjects” as defined by DHHS regulations.DHHS regulations.

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 development, testing and evaluation, designed to develop or contribute to generalizable to develop or contribute to generalizable knowledge.”knowledge.”

Belmont Report Definition of ResearchBelmont Report Definition of Research““Any activity designed to test a hypothesis, Any activity designed to test a hypothesis, permit conclusions to be drawn and thereby to permit conclusions to be drawn and thereby to develop or contribute to generalizable develop or contribute to generalizable knowledge (expressed, for example, in theories, knowledge (expressed, for example, in theories, principles, and statements of relationships).”principles, and statements of relationships).”

DHHS Definitions (con’t)DHHS Definitions (con’t)

B. Human Subjects:B. Human Subjects:

““A living individual about whom an A living individual about whom an investigator conducting research obtains investigator conducting research obtains (1) data through intervention or (1) data through intervention or interaction with the individual; or (2) interaction with the individual; or (2) identifiable private information.”identifiable private information.”

DHHS Definitions (con’t)DHHS Definitions (con’t)

Intervention:Intervention:Includes both the physical procedures by Includes both the physical procedures by which data are gathered (eg. blood draw) which data are gathered (eg. blood draw) and manipulations of the subject or the and manipulations of the subject or the subject’s environment that are performed subject’s environment that are performed for research purposes for research purposes

Interaction:Interaction:

Includes communication or interpersonal Includes communication or interpersonal contact (eg. questionnaires, interviews) contact (eg. questionnaires, interviews) between the investigator and subjectbetween the investigator and subject

DHHS Definitions (con’t)DHHS Definitions (con’t) Private Information:Private Information:

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

Food and Drug Food and Drug Administration (FDA) Administration (FDA) Definition of Human Definition of Human

Subject ResearchSubject Research

FDA has different definitions of FDA has different definitions of “research” and “human subjects”“research” and “human subjects”

FDA guidelines must be followed FDA guidelines must be followed when using a drug or device in the when using a drug or device in the studystudy

History of Development of History of Development of Human Research Human Research

ProtectionsProtections1.1. 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 Originally designed to make treatment available

to African-American men with syphilis, even to African-American men with syphilis, even though there was no known effective treatmentthough there was 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 After penicillin was proven an effective treatment ’40’s), men were denied antibiotics and prevented ’40’s), men were denied antibiotics and prevented treatment from military and local physicianstreatment from military and local physicians


ProtectionsProtections2.2. US Food, Drug and Safety Act US Food, Drug and Safety Act

(1938)(1938)

107 people died after taking 107 people died after taking sulfanilamide, a cold remedy that sulfanilamide, a cold remedy that contained anti-freeze. contained anti-freeze.

This act enforces manufacturers to This act enforces manufacturers to demonstrate drug safety.demonstrate drug safety.


ProtectionsProtections3.3. Nuremberg Code (1947)Nuremberg Code (1947)

Result of the trial of Nazi doctors and Result of the trial of Nazi doctors and scientists from WWII – no guidelines for scientists from WWII – no guidelines for human researchhuman 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


ProtectionsProtections3.3. Nuremberg Code (con’t)Nuremberg Code (con’t)

Problems:Problems:1.1. Little impact on research done in the US – Little impact on research done in the US –

thought to condemn Nazisthought to condemn Nazis

2.2. No strength of the law behind itNo strength of the law behind it

3.3. Only applied to non-therapeutic human Only applied to non-therapeutic human subject researchsubject research


ProtectionsProtections4.4. Declaration of Helsinki (1964)Declaration of Helsinki (1964)

Code of ethics developed by the World Code of ethics developed by the World Medical Association (now known and World Medical Association (now known and World Health Org)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 Journals required all published research to

follow Declaration’s guidelinesfollow Declaration’s guidelines


ProtectionsProtections5.5. 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 established the National Commission for the Protection of Human Subjects of the Protection of Human Subjects of Biomedical and Behavioral ResearchBiomedical and Behavioral Research

Purpose of The National Commission:Purpose of The National Commission:

1.1. Identify basic ethical principles underlying Identify basic ethical principles underlying the conduct of human subject researchthe conduct of human subject research

2.2. Develop guidelines to ensure conduct of Develop guidelines to ensure conduct of human subject research in accordance human subject research in accordance with those principleswith those principles


ProtectionsProtections5.5. 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 Research”; Issued by the Department of Health, Education and Welfare (later renamed Health, Education and Welfare (later renamed DHHS)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 By 1991, 16 other federal

agencies/departments applied 45 CFR 46 to agencies/departments applied 45 CFR 46 to research they fund/conductresearch they fund/conduct

Referred to as the “Common Rule”Referred to as the “Common Rule”


ProtectionsProtections6.6. The Belmont Report (1979)The Belmont Report (1979)

Issued by the National Commission for Issued by the National Commission for the Protection of Human Subjects of the Protection of Human Subjects of Biomedical and Behavioral ResearchBiomedical and Behavioral Research

Purpose: resolve ethical problems that Purpose: resolve ethical problems that surround the conduct of human surround the conduct of human subject researchsubject research

One principle does not outweigh One principle does not outweigh another; each has equal weightanother; each has equal weight


ProtectionsProtections6.6. The Belmont Report (con’t)The Belmont Report (con’t)

The three principles:The three principles:1.1. Respect for Persons – treat people as Respect for Persons – treat people as

autonomous creatures and not a autonomous creatures and not a means to an end; provide extra means to an end; provide extra protection for those with limited protection for those with limited autonomy autonomy

Requires informed consentRequires informed consent Requires respect of privacy of research Requires respect of privacy of research

subjectssubjects



The three principles:The three principles:2.2. Beneficence – minimize harm and Beneficence – minimize harm and

maximize benefitmaximize benefit Requires use of the best possible research Requires use of the best possible research

design to maximize benefit and minimize design to maximize benefit and minimize harmharm

Requires researchers to be able to perform Requires researchers to be able to perform the procedures and manage the risksthe procedures and manage the risks

Prohibits research without a favorable risk-Prohibits research without a favorable risk-benefit ratiobenefit ratio



The three principles:The three principles:3.3. Justice – treat all people fairly and Justice – treat all people fairly and

ensure burdens and benefits are shared ensure burdens and benefits are shared equitablyequitably

Requires equitable selection of research Requires equitable selection of research subjectssubjects

Requires avoidance of exploitation of Requires avoidance of exploitation of vulnerable populations or populations of vulnerable populations or populations of convenience (ie pregnant women; children; convenience (ie pregnant women; children; incarcerated populations)incarcerated populations)


ProtectionsProtections7.7. International Conference on International Conference on

Harmonisation - ICH (1990)Harmonisation - ICH (1990) Joint regulatory/industry project to Joint regulatory/industry project to

improve process of developing new improve process of developing new products between Japan, Europe and products between Japan, Europe and United StatesUnited States

Allows for international research studies to Allows for international research studies to follow same rules/regulationsfollow same rules/regulations

Conference convenes to update regulationsConference convenes to update regulations Established “Good Clinical Practices” Established “Good Clinical Practices”

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, Standard for the design, conduct,

performance, monitoring, analyses and performance, monitoring, analyses and reporting of research reporting of research

Even though established for drug studies, Even though established for drug studies, they dictate appropriate conduct for all they dictate appropriate conduct for all researchresearch

Innovative Practice vs. Innovative Practice vs. ResearchResearch

Innovative clinical practice is an intervention Innovative clinical practice is an intervention designed solely to enhance the well-being of an designed solely to enhance the well-being of an individual patient or client. The purpose is to individual patient or client. The purpose is to provide diagnosis, preventative treatment, or provide diagnosis, preventative treatment, or therapy to particular individuals.therapy to particular individuals.

Considered “research” only if previous criteria is Considered “research” only if previous criteria is met.met.

At UPMC, the introduction of innovative At UPMC, the introduction of innovative procedures or therapies into clinical practice procedures or therapies into clinical practice (when research is not involved), requires review (when research is not involved), requires review by department chair and the UPMC Technology by department chair and the UPMC Technology Assessment Committee/Innovative Practices Sub-Assessment Committee/Innovative Practices Sub-Committee prior to implementation.Committee prior to implementation.

Quality Assurance vs. Quality Assurance vs. ResearchResearch

Precise definitions to permit the distinction Precise definitions to permit the distinction between research studies and quality between research studies and quality assurance projects are difficult and have not assurance projects are difficult and have not been established. In general, a quality been established. In general, a quality assurance project is a project that is focused assurance project is a project that is focused primarily on improving patient care within a primarily on improving patient care within a given patient care environment and, as such, given patient care environment and, as such, the outcome may not be generalizable to the outcome may not be generalizable to other patient care environments.other patient care environments.

Both UPMC and CHP require the submission Both UPMC and CHP require the submission of all quality assurance projects for review.of all quality assurance projects for review.

Questions to distinguish QA from Questions to distinguish QA from ResearchResearch

(any yes response indicates (any yes response indicates research)research)

1.1. Is there a commitment, in advance of data collection, to Is there a commitment, in advance of data collection, to a corrective plan given any one of a number of study a corrective plan given any one of a number of study outcomes? Does the PI of the study have both clinical outcomes? Does the PI of the study have both clinical supervisory responsibility and the authority to impose supervisory responsibility and the authority to impose change?change?

2.2. Is the research being sponsored/funded by an external Is the research being sponsored/funded by an external agency?agency?

3.3. Does the proposed study involve the prospective Does the proposed study involve the prospective assignment of patients to different procedures or assignment of patients to different procedures or therapies based on a predetermined plan?therapies based on a predetermined plan?

4.4. Does the proposed study involve a “control group” in Does the proposed study involve a “control group” in whom the therapeutic or study intervention is whom the therapeutic or study intervention is intentionally withheld to allow an assessment of its intentionally withheld to allow an assessment of its efficacy?efficacy?

Questions to distinguish QA from Questions to distinguish QA from ResearchResearch

5.5. Will the study intervention be delivered in a blinded Will the study intervention be delivered in a blinded fashion wherein neither the physician nor the patient fashion wherein neither the physician nor the patient knows to whom the study intervention or comparative knows to whom the study intervention or comparative intervention (eg. standard care, placebo) was given?intervention (eg. standard care, placebo) was given?

6.6. Is the assessment of outcome blinded to the study Is the assessment of outcome blinded to the study intervention for purpose of establishing the efficacy of intervention for purpose of establishing the efficacy of the intervention?the intervention?

7.7. Does the proposed study involve the prospective Does the proposed study involve the prospective evaluation of a drug, biologic or device that is not evaluation of a drug, biologic or device that is not currently approved for general use by the FDA?currently approved for general use by the FDA?

8.8. Will patients involved in the proposed study be exposed Will patients involved in the proposed study be exposed to additional risks or burdens beyond standard clinical to additional risks or burdens beyond standard clinical practice in order to make the results of the study practice in order to make the results of the study generalizable?generalizable?

Types of Study DesignsTypes of Study Designs

1.1. Observational DesignsObservational Designs

Types of Observational Types of Observational StudiesStudies

Cohort StudiesCohort Studies A group of subjects followed over timeA group of subjects followed over time Purpose: defining the incidence and Purpose: defining the incidence and

investigating potential causes of a condition investigating potential causes of a condition (incidence)(incidence)

Can be prospective – investigator chooses a Can be prospective – investigator chooses a sample group and measures characteristics in sample group and measures characteristics in each subject over a period of time that might each subject over a period of time that might predict outcomespredict outcomes

Can be retrospective – same as prospective, Can be retrospective – same as prospective, except all data collection and follow-up has except all data collection and follow-up has happened in the past; only possible if adequate happened in the past; only possible if adequate data is availabledata is available


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 measurements are made at one time point with no follow-uppoint with no follow-up

Purpose: describing variables and their Purpose: describing variables and their distribution patterns (prevalence)distribution patterns (prevalence)

Strength – fast and inexpensive since Strength – fast and inexpensive since there is no follow-up or waiting time for there is no follow-up or waiting time for outcomeoutcome


Case-Control StudiesCase-Control Studies Two groups of people examined for the Two groups of people examined for the

same outcomesame outcome Group 1 – “cases” or a population of people Group 1 – “cases” or a population of people

with a certain diseasewith a certain disease Group 2 – “controls” or a population of people Group 2 – “controls” or a population of people

without that same disease without that same disease Purpose: compare prevalence of risk Purpose: compare prevalence of risk

factor(s) in subjects with the disease factor(s) in subjects with the disease (cases) versus subjects without the disease (cases) versus subjects without the disease (controls) (controls)

Types of Study DesignsTypes of Study Designs

1.1. Observational DesignsObservational Designs

1.1. Experimental Designs – Experimental Designs – interventional studiesinterventional studies

Experimental StudiesExperimental Studies

These studies evaluate the effects of These studies evaluate the effects of an interventionan intervention Types of interventions:Types of interventions:

Behavior modification (eg. a walking Behavior modification (eg. a walking program to improve weight loss)program to improve weight loss)

Drug (eg. a new investigational drug or Drug (eg. a new investigational drug or studying a drug for off-label use – subject to studying a drug for off-label use – subject to FDA regulations)FDA regulations)

Device (eg. a new investigational stent – Device (eg. a new investigational stent – subject to FDA regulations)subject to FDA regulations)

Strength: Can demonstrate causalityStrength: Can demonstrate causality

Phases of Experimental Phases of Experimental StudiesStudies

Phase I:Phase I:Unblinded studies of a small number of Unblinded studies of a small number of healthy volunteers to test safety of healthy volunteers to test safety of treatment (can sometimes use people treatment (can sometimes use people with the disease)with the disease)

Phase II:Phase II:Randomized studies of relatively small Randomized studies of relatively small number of people with the disease to test number of people with the disease to test dose ranges and/or efficacy of treatment dose ranges and/or efficacy of treatment

Phases of Experimental Phases of Experimental StudiesStudies

Phase III:Phase III:Randomized studies of large number of Randomized studies of large number of people with the disease to test efficacy of people with the disease to test efficacy of treatment on pre-selected outcomestreatment on pre-selected outcomes

Phase IV:Phase IV:Large experimental studies or Large experimental studies or observational studies conducted after observational studies conducted after treatment has been approved by the FDA treatment has been approved by the FDA to assess performance of treatment to assess performance of treatment (called Post-Market Studies)(called Post-Market Studies)

Do I really want Do I really want to conduct to conduct

clinical research?clinical research?

What Help is Available?What Help is Available?

University of Pittsburgh IRB/RCCOUniversity of Pittsburgh IRB/RCCO IRB Coordinators – wealth of knowledge; IRB Coordinators – wealth of knowledge;

will perform an informal review prior to will perform an informal review prior to official reviewofficial review

www.irb.pitt.edu – IRB manual; required – IRB manual; required forms; link to research training website; etc.forms; link to research training website; etc.

Sponsored educational activities – monthly Sponsored educational activities – monthly “Ask the IRB” sessions; conferences on “Ask the IRB” sessions; conferences on current issues; etc.current issues; etc.

Human Immunology Research OfficeHuman Immunology Research Office

Human Immunology Human Immunology Research OfficeResearch Office

Assistance with investigational human Assistance with investigational human studies involving transplantation that studies involving transplantation that are initiated by STI research or are initiated by STI research or involves substantial support from STI involves substantial support from STI researchresearch

Act as repository for all documents Act as repository for all documents related to above studies and all other related to above studies and all other studies requiring STI research studies requiring STI research participation (eg. Processing of blood participation (eg. Processing of blood samples on 15samples on 15thth floor BST floor BST


Services Available:Services Available:1.1. Consultation regarding clinical Consultation regarding clinical

aspects/logistics of new projectsaspects/logistics of new projects

2.2. IRB summary protocol and consent IRB summary protocol and consent form preparation assistanceform preparation assistance

3.3. Project coordination:Project coordination: Assist with recruitment based on projectAssist with recruitment based on project Ensure proper handling of Ensure proper handling of

samples/specimens from patient to labsamples/specimens from patient to lab


Information to be stored in this office:Information to be stored in this office:1.1. Copies of all current and future IRB Copies of all current and future IRB

submissionssubmissions

2.2. Correspondence between IRB and Correspondence between IRB and investigators including approval letters, audit investigators including approval letters, audit reports, etcreports, 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


To request assistance:To request assistance:1.1. Contact office to set up meeting to Contact office to set up meeting to

discuss project, assistance requested, etcdiscuss project, assistance requested, etc

2.2. Complete research outline (template will Complete research outline (template will be supplied by the office)be supplied by the office)

Contact information:Contact information:

Location: E1540 BSTLocation: E1540 BST

Phone: 412-624-6611Phone: 412-624-6611

Email: [email protected]: [email protected]

Requirements Prior to IRB Requirements Prior to IRB SubmissionSubmission

Possible UPMC fiscal approvalPossible UPMC fiscal approval STI PRC (protocol review committee) STI PRC (protocol review committee)

approval approval Any protocol submitted to the IRB requires Any protocol submitted to the IRB requires

prior scientific review; PRC review includes prior scientific review; PRC review includes scientific review.scientific review.

submission is reviewed both by an submission is reviewed both by an investigator and a research coordinatorinvestigator and a research coordinator

Facilitator of committee is Agnes Zachoszcz Facilitator of committee is Agnes Zachoszcz (all submissions are emailed to her)(all submissions are emailed to her)

Documents

Basics of Clinical Research