Ethical Issues in Translational Research Emma A. Meagher, MD emma@gcrc.upenn.edu

Clinical Care vs. Research provide direct benefit to the patient Research Contribute to generalizable knowledge Medicine depends on research to elucidate mechanism of disease and identify treatment strategies Special attention to possible harm to the subject Regulatory codes place the responsibility for the ethical conduct of research primarily on the shoulders of the researchers

Research Interfaces

The Evolution of HSR Standards 1947 – Nuremberg Code 1964 – Declaration of Helsinki 1979 – Belmont Report DHHS and FDA to adopt regulatory requirements for IRB review (1981) 1991 – The Common Rule Now codified by 18 federal agencies 1997 – Good Clinical Practices

The Belmont Report Purpose of the report is to provide three principles (prescriptive judgments) to assist researchers, subjects, reviewers and interested citizens with an understanding of the ethical issues inherent in HSR Statement consists of 3 parts Distinction between research and medical practice Establishment of 3 ethical principles Remarks regarding application of the principles

The Belmont Report Practice Research Interventions designed solely to enhance the wellbeing of the patient and that have a reasonable expectation of success Research An activity designed to test an hypothesis, permit conclusions to be drawn, develop or contribute to generalizable knowledge

The Belmont Report Three Ethical Principles Principle of respect for persons autonomy Principle of beneficence Principle of justice

Respect for Persons Autonomy Enters research voluntarily and with adequate information Implies everyone is capable of self determination Matures during life span May be lost in whole or in part as a result of illness, mental disability or circumstances that restrict liberty Cannot exclude those incapable of self determination Respect for such situations requires protection Explicit requirement that each class of incompetent patient be considered on its own terms Third parties whose primary goal is to protect the subject from harm should be used and that these individuals be allowed to observe the research

The Belmont Report - Three Ethical Principles Principle of respect for persons autonomy Principle of beneficence Principle of justice

Beneficence Acts of kindness or charity that go beyond strict obligation Strict sense of obligation Do not harm Maximize possible benefits Minimize possible harms Seek benefit despite certain risks Benefits should be forgone because of the risk Requires a risk benefit assessment be made

The Belmont Report - Three Ethical Principles Principle of respect for persons autonomy Principle of beneficence Requires a risk benefit assessment be made Principle of justice Fairness in selection of subjects Potential benefit is denied Burden is imposed

How to Apply the 3 Principles Autonomy - Informed consent Information Comprehension Voluntariness Beneficence – determination of the risk and benefits Investigator – study design Peer review – risks are justified Subject – the determination to participate Justice Selection of subjects described by the researcher Reviewed during the peer review process Determined to be equitable

The Evolution of HSR Standards 1947 – Nuremberg Code 1964 – Declaration of Helsinki 1979 – Belmont Report DHHS and FDA to adopt regulatory requirements for IRB review (1981) 1991 – The Common Rule Now codified by 18 federal agencies 1997 – Good Clinical Practices

The Common Rule Requires institutional assurance of compliance First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds Mandates role of the IRB Defines requirements for informed consent Codifies special requirements for vulnerable populations Pregnant women, fetuses, IVF subpart A Prisoners –subpart C Children –sub part D Requires institutional assurance of compliance

Responsibility of the IRB Protect the rights and welfare of research subjects Oversight of the conduct of ALL human research Guidance and support to research staff through IRB review and administrative IRB support staff Ensures compliance with all federal, state, local and institutional requirements in human subject research

Risk/Benefit Analysis IRB Decision Matrix BENEFICENCE JUSTICE RESPECT FOR PERSONS Risk/Benefit Analysis Experimental Design Qualifications of PI Subject selection Inclusion/exclusion Recruitment The application of these general principles leads to the 3 requirements of informed consent, risk/benefit assessment and just selection of subjects for research. Privacy & Confidentiality Protection of subjects (especially vulnerable populations) Informed consent Surrogate consent Assent

Expanded IRB Decision Matrix Seven Principles Social or scientific value Scientific validity Fair subject selection Favorable risk benefit ratio Independent review Informed consent Respect for autonomy

The Common Rule Requires institutional assurance of compliance First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds Mandates role of the IRB Defines requirements for informed consent Codifies special requirements for vulnerable populations Pregnant women, fetuses, IVF subpart A Prisoners –subpart C Children –sub part D Requires institutional assurance of compliance

Elements of Informed Consent Purpose Methods and procedures Painstakingly precise Risks and discomforts Known and unknown Risks of disease versus research participation Benefits Promise of benefit Alternatives to participation Decision relative to their own clinical condition Voluntary and uncoerced Payment considerations Cost consideration

Elements of Informed Consent Other considerations Study discontinuation by sponsor / FDA / investigator Participation discontinuation by participant Participation discontinuation by investigator Injury during a study Standard language concerning liability Use of personal Information Privacy HIPPA Human Subjects rights

The Common Rule Requires institutional assurance of compliance First time after more than 25 years in the making a comprehensive regulatory framework existed that formally governed all human subjects research conducted by the federal government or in facilitates receiving federal funds Mandates role of the IRB Defines requirements for informed consent Codifies special requirements for vulnerable populations Pregnant women, fetuses, IVF subpart A Prisoners –subpart C Children –sub part D Requires institutional assurance of compliance

The Evolution of HSR Standards 1947 – Nuremberg Code 1964 – Declaration of Helsinki 1979 – Belmont Report DHHS and FDA to adopt regulatory requirements for IRB review (1981) 1991 – The Common Rule Now codified by 18 federal agencies 1997 – Good Clinical Practices

Good Clinical Practice (GCP) Provides: “ A unified standard for the design, conduct, recording, and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected”. Have been adopted by industry and academia worldwide Clinical research must be conducted in a scientifically sound and ethical manner whether it is intended for regulatory submission (FDA) or not

Which Regulations Apply and When? FDA: research involves products regulated by FDA (Title 21) Common Rule: Federally supported or conducted or conducted in an institution that agrees to review all research under the Common Rule (CFR 46) Both: if Federally funded research involves FDA regulated product or FDA regulated research conducted in an institution that agrees to review all research under the Common Rule Common Rule FDA

Your Responsibility as an Investigator 21 CFR 50 Informed Consent 56 IRB Regulations 54 Financial Disclosure 312 Investigational New Drug 314 New Drug Application 600 Biological Products 812 Investigational Device Exemptions 45 CFR Part 46 DHHS Human Subjects Regulations Social or scientific value Scientific validity Fair subject selection Favorable risk benefit ratio Independent review Informed consent Respect for autonomy

GCP Defines Responsibilities of the investigator and/or sponsor What is a clinical research protocol? Requirement for informed consent and how to obtain it Requirements for adverse event reporting Interactions with IRB Regulations governing the use of investigational drugs

13 Principles of Good Clinical Practices Trials are conducted in accordance with the ethical principles of the Declaration of Helsinki and consistent with GCP and other applicable regulations. The risks and inconveniences of the trials should be weighed against the benefit. Subject’s rights, safety and well-being prevail over science and society’s interest. Available information on the investigational product should be adequate to support the study.

13 Principles of Good Clinical Practices Clinical trials should be scientifically sound and described in a clear concise protocol The trial should be conducted in accordance with an IRB approved protocol Medical decisions and care of the subject is always the responsibility of a qualified physician Study team members should be qualified through education, training and experience to perform their study related tasks.

13 Principles of Good Clinical Practices Informed consent should be obtained from every subject before participation All trial information should be recorded, handled and stored to ensure accurate reporting, interpretation and verification. The confidentiality of records should be protected thus respecting the privacy and confidentiality of subjects. Investigational products should be manufactured, stored and handled in accordance with GMPs. Systems with procedures that assure the quality of every aspect of the trial should be implemented.

GCP and the Clinical Protocol A clinical protocol for GCP addresses the Science Background, rationale, study design, statistics Human subjects protection Autonomy, beneficence, justice, One step further it defines the procedures Study procedures (time and event charts, dose escalation schedules) Data collection/recording/storage/reporting/analysis Monitoring / AE reporting Requirement for case report forms

7 Rules of a Good Protocol Clearly identify your primary objective - there should be only one primary objective - it will drive the sample size. - secondary objectives can be multiple Tell the story of the study in the rationale Why are you doing the study? What is the logic? What do you hope to demonstrate? Design your study to achieve the primary objective study procedures, study design, statistical analysis, use of control

7 Rules of a Good Protocol Ensure consistency from section to section “The devil is the details” Give clear directions for each step of the protocol Consider the relationship of one procedure on another Develop a flow sheet for study day or week State how the data will be handled and analyzed Carefully consider the conditions of the evaluations performed in the study Avoid unnecessary measures, how often does a blood sample need to to taken?

GCP - 7 Rules of Good Protocol Safety For novel compounds, does the toxicology in animals cover the dose and duration in humans? Has the route of dosing been studied in animals? How will subject’s safety be evaluated, by whom, how often? How will severe/serious events be evaluated? Define AE and SAE and their reporting requirements. How will the study be monitored?

Summary Research conduct directed by existence of two sets of federal guidelines GCP and the Common Rule Both are centered on the 3 fundamental pillars of research ethics Both mandate Informed consent Peer Review Standards for clinical trial conduct

Research Interfaces

Upholding ethical responsibility Autonomy - Informed consent Information Comprehension Voluntariness Beneficence – determination of the risk and benefits Peer review – risks are justified Investigator – study design Subject – the determination to participate Justice Selection of subjects described by the researcher Reviewed during the peer review process Determined to be equitable