Ethics and Conflict of Interest – Concepts and Case Studies

David T. Rubin, MD Joseph B. Kirsner Professor of Medicine

Chief, Section of Gastroenterology, Hepatology and Nutrition

Associate Faculty, MacLean Center for Clinical Medical Ethics

Disclosures

Consultant and/or Grant Support • Abbvie

• Amgen

• Celgene

• Emmi

• Forward Pharma

• Genentech

• Janssen

• Pfizer

• Prometheus

• Sandoz/Novartis

• Shire

• Takeda

Board Membership/Other

• ACG Board of Trustees

• CFO, Secretary, Cornerstones Health, Inc (non-profit medical education organization)

• GoDuRn, LLC, Co-Founder

Hans Jonas, “Philosophical Reflections on Experimenting with Human Subjects“, 1970

Let us all remember that a slower progress in the conquest of disease would not threaten society,

grievous as it is to those who deplore that particular disease be not yet conquered but that, society would indeed be threatened by the erosion of those moral values whose loss, possibly caused by too ruthless a pursuit of scientific progress, would make its most

dazzling triumphs not worth having.

Early Codes of Research Ethics

470-360 B.C.E.

Hippocratic Oath:

Physician-Patient Relationship

1803

Thomas Percival: Specific Directives about Research Ethics; specific

directives to physicians planning to perform human experiments

1803

William Beaumont: Non-Therapeutic Experimentation; oldest American document dealing with ethics of

human experimentation; acceptable experimental risk

1865

Claude Bernard: An Introduction to the Study of

Experimental Medicine; scientific method and therapeutic research;

acceptable experimental risk

1947

Nuremburg Code: International code

differentiating between legal and illegal human experimentation

1979

Belmont Report: Ethical principles of

biomedical and behavioral research with

human subjects

Nuremberg Code, 1947

• Established in response to Nazi war atrocities during WWII

• Key principles:

• Voluntary consent is essential.

• The experiment must yield fruitful results for the good of society, unprocurable by other methods or means, and not random and unnecessary in nature.

• The experiment should avoid all unnecessary physical and mental suffering and injury.

• Risk should not exceed the humanitarian importance of the problem to be solved.

• The human subject should be at liberty to bring the experiment to an end.

Unethical Research Practices

• Maurice Pappworth, MD, Human Guinea Pigs, 1967. (U.K.)

– 100s of unethical research practices. – Named names!

• Henry K Beecher, MD

– 22 studies; 4 involved children. – Did not identify researchers,

institutions, or journal in which study published.

Beecher HK. Ethics and clinical research. N Engl J Med. 1966;274:1360-4.

“An experiment is ethical or not at its inception…ends do not justify means.”

Beecher HK. Ethics and clinical research. N Engl J Med. 1966;274:1360-4.

Jewish Chronic Disease Hospital, NYC

• In 1963, chronically ill and debilitated non-cancer were injected with live human cancer cells.

• Physicians did not inform the patients so as not to scare them, since it was believed that the cells would be rejected.

• Data compared to healthy volunteers (Prisoners)

• Defense argued that the risks were minimal, but…

• On cross-examination, Dr. Southam (one of the physicians charged) specifically said he would not be injected.

• “It would be stupid for a cancer doctor to take such risks when others are available…”

Katz J. New York: Russell Sage Foundation. 1972:9-65.

Tuskegee Syphilis Study USPHS Syphilis Study (Tuskegee)

• 1932: 200-300 black males who had syphilis in Macon County, AL

– Deception at the start: Claimed there would be treatment.

• When penicillin became available, subjects were not offered treatment

• Physicians discouraged from treating these men if they came in for treatment

• Study continued for > 40 years – Interim data and methods published in medical journals.

– Study only stopped after publicized in lay press.

• 1997: Apology from President Clinton: “The United States government did something that was wrong—deeply, profoundly, morally wrong.”

Thomas SB. Encyclopaedia Britannica. Accessed Feb 29 2016.

The Belmont Report, 1979

• Three Principles – Autonomy – Beneficence – Justice

• Application – Informed Consent – Assessment of Risks and

Benefits – Selection of Subjects

Autonomy Beneficence Justice

Jonsen AR, Siegler M, Winslade WJ. Clinical Ethics, 4th ed. 1998.

• National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Medical Factors (beneficence)

Patient

Preferences (autonomy)

Quality of Life External

Considerations (Justice)

Jonsen, Siegler, Winslade. Clinical Ethics, 4th ed. 1998.

Practical Clinical Medical Ethics: “The Four Box Model”

Medical Factors

Beneficence and

Nonmaleficence

• What is the medical

problem? Dx? Px?

• Is this acute? Chronic?

Critical? Emergent?

Reversible?

• What are the goals of

treatment?

• What are the probabilities of

success?

• What are the plans in case

of therapeutic failure?

• How can harm be avoided?

Structured Medical Decision Making

Patient

Preferences

Respect for Autonomy: Right

to Choose

• Pt. mentally capable,

competent?

• What is patient stating about

preferences for treatment?

• Has patient been informed of

benefits/risks, understood this

information and given consent?

• If incapacitated, who is

surrogate? Is this person using

appropriate standards for

decision making?

• Are there advance directives?

Structured Medical Decision Making

Quality of Life

Beneficence/Nonmaleficence/

Respect for Autonomy • Prospects for return to normal

life? (with and without Rx)

• What physical, mental and

social deficits is the patient to

experience if treatment

succeeds?

• Are there biases that might

prejudice provider’s evaluation

of pt. QOL?

• Is the pt’s present or future

condition such that his or her

continued life might be judged

undesirable?

• Are there plans to forgo

treatment? For

comfort/palliation?

Structured Medical Decision Making

External

Considerations

Loyalty/Fairness

• Family issues

• Provider issues

• Financial/economic factors

• Religious/cultural factors

• Limits on confidentiality?

• Problems of allocation of

resources?

• How does the law affect

treatment decisions?

• Is clinical research/teaching

involved?

• Conflict of interest on the part of

the providers or the institution?

Structured Medical Decision Making

U.S. Code of Federal Regulations Title 45 Part 46 (1981, rev. 1991, 2001)

• Outlines federal policy for the protection of human subjects in research

• Establishes mandate for Institutional Review Boards (IRBs)

• Discusses additional protections for vulnerable populations (pregnant women, human fetuses, neonates, prisoners, and children)

Fed Regist. 2005. Codified at 45 CFR §46.

• Research studies include: • Invasive or non-invasive procedures including removal of body tissues or

fluids • Administration of drugs • Exposure to various forms of radiation • Alteration of diet or environment • Interviews/ surveys

• NOT research: • Case studies • Works of journalism

• Quality assurance data may or may not be research. • Depends on what you will do with the research.

U.S. Code of Federal Regulations Human Subjects Protections

Fed Regist. 2005. Codified at 45 CFR §46.

• Specifies requirements for informed consent – Specifies surrogate decision-making

• Dual Purposes of IRBs: – Ensure that research is scientifically sound;

– Ensure human subjects protections

• Ensure safety (risks are minimized)

• Respect for subject’s autonomy (informed consent)

• IRB Composition: – Sufficient scientific and technical expertise

– Non-scientific members

– Unaffiliated (independent) members

U.S. Code of Federal Regulations Subpart A: The Common Rule

Fed Regist. 2005. Codified at 45 CFR §46.

U.S. Code of Federal Regulations Vulnerable Populations: Special Protections

• Subpart B: Pregnant women and fetus

• Subpart C: Prisoners

• Subpart D: Children

Why Do We Need Industry-Sponsored Clinical Trials?

• No NIH-sponsored study has brought a new drug to the market

• Developing and studying a drug in clinical trials is expensive

• Estimated $2.6B to bring a drug to market

Mullin R. http://www.scientificamerican.com/article/cost-to-develop-new-pharmaceutical-

drug-now-exceeds-2-5b/. Accessed March 1, 2016.

Clinical Trial Phases

Trial Phase Goal Population

Phase I Evaluate safety, safe dosage range, identify side effects

Small group

Phase II Efficacy and safety Larger group

Phase III Effectiveness compared to other treatments; minor side effects

Large groups

Phase IV Post-marketing in various populations and long-term side-effects

Various populations

Clinicaltrials.gov. http://www.nlm.nih.gov/services/ctphases.html. Accessed February 22, 2016.

An Example of a Phase-1 Clinical Trial

Potential for Conflict of Interest

• A phase-I Industry Sponsored Clinical Trial for a monoclonal antibody drug to treat breast cancer.

• Actual per patient cost to the university: $21,800

• Per patient cost (including indirect costs): $22,100

• Per patient costs received from industry: $110,000

• Earned by the university: $66,700

Medical Factors

(beneficence)

Patient Preferences

(autonomy)

Quality of Life

External

Considerations

(Justice)

Ethics of Clinical Trials

• Being a moral fiduciary

– Professional relationship

– Patients trust their researcher to do what is right

• Remove conflict of interest whenever possible

– Is the scientific question worth pursuing?

– Is the question relevant to the population studied?

– Is this an appropriate use of resources?

• Moral vs. Legal: Not always concordant

Clinical Trials

• Procedures and related risks or side-effects should be explained.

• In phase II trials, important to explain to patient that any therapeutic benefit hoped for may or may not transfer into benefit for the patient with respect to increased outcomes or improved HRQoL.

• Since phase III trials are comparative, all options should be explained to patients in details before randomization as knowledge of the assignment may influence the way in which an investigator explains the alternatives.

Machin D, Campbell MJ. Design of studies for medical research. 2005.

Recruitment

• Incentives for investigators

– Ownership

– Finders fees

– Disclosure: What is the impact on trust if true disclosure is released?

→ 21 CFR Part 56: Financial disclosure by investigators and code of federal regulation

• Compensation for subjects

• Therapeutic misconception

– Patients don’t understand what’s being done

– “My doctor selected this for me”

Informed Consent: Case of Jesse Gelsinger

• Jesse Gelsinger had a mild form of ornithine transcarbamylase OTC deficiency1

• September 1999: At age 18, enrolled in clinical trial at the University of Pennsylvania to test the safety of a gene therapy procedure.

– “Altruistic trial participant”2

– Involved injection of adenoviral vector with corrected gene

– Few days later, Jesse suffered severe immune reaction, multiple organ failure and brain death

• Informed consent failed to mention:2

– The serious side effects experienced by other participants

– The results of the pre-clinical study on monkeys (risk of clotting)

– The financial disclosures of the investigators

1Jesse’s Intent. Guinea Pig Zero. http://www.guineapigzero.com/jesses-intent.html Accessed December 13, 2016. 2Sibbald B. CMAJ. 2001;164(11):1612.

• His father wrote about his son’s story “Jesse’s Intent” in the Guinea Pig Zero magazine.1

– “Dr. Batshaw and I never discussed the dangerous side of this work.”

– “They are heartless and soulless industry and their lobbying efforts; they are the politicians more interested in placating industry than in protecting the people, they are doctors so blinded in their quest for recognition that they can't even see the dangers anymore. Let them apply Jesse's intent to their efforts, and then they'll get it right.”

• Since then, FDA implemented changes:2

– Requires sponsors’ (investigators’) financial disclosures and conflicts of interest before initiation of trial, compared to previously when it did not require these until application for approval or licensure of products.

1Jesse’s Intent. Guinea Pig Zero. http://www.guineapigzero.com/jesses-intent.html Accessed December 13, 2016. 2Sibbald B. CMAJ. 2001;164(11):1612.

Informed Consent: Case of Jesse Gelsinger

Clinical Trials Reporting: a Case Study

• Phase 3 study of a novel steroid for UC

• Multi-center, placebo controlled

• PI (me) emails and contacts investigators regularly to encourage study participation.

• Study completed, data locked

• Company that was licensing the drug to the US company goes bankrupt. Lawyers decide that the value of the company may be affected based on the results of the trial.

• The results are therefore never analyzed.

Clinical Trials Reporting: a Case Study

• PI (me) contacts company every 6 months for 5 years (!!)

• Company has new leadership, they know nothing.

• Ask their lawyers to look into it – Weeks go by – I express great concern that patients and investigators should be notified of

results – Told that “we can’t find any of the data”

• A letter is sent to investigators apologizing and telling them no results will ever be determined.

FDA on Clinical Trials Reporting and Publication

• How to balance the potential beneficial public health effects of requiring that clinical trials data be made public with the burdens that such requirements may place on companies and their innovation.

– Companies may lose a competitive advantage if their competitors are alerted to their clinical trials activities and failures.

– The public may be harmed if a particular type of clinical trial is repeated

– If clinical trial data are to be made public, the timing and contents of the disclosure may prove to be pivotal, both with respect to competitive innovation and public safety.

Williams E. Clinical Trials Reporting and Publications. Congressional Reports Order Code RL32832, July 2007.

FDA on Clinical Trials Reporting and Publication

• Federal regulations require the publication of certain clinical trial information and encourage the disclosure of some results

• Other organizations have requirements: – World Health Organization (WHO)

– The International Committee of Medical Journal Editors (ICMJE)

– American Medical Association (AMA)

– The Association of American Medical Colleges (AAMC)

– The Institute of Medicine (IOM)

– The pharmaceutical industry favors limited, voluntary clinical trial

registration and reporting

Williams E. Clinical Trials Reporting and Publications. Congressional Reports Order Code RL32832, July 2007.

THE WALL STREET JOURNAL. OPINION DECEMBER 30, 2008

The FDA Is Killing Crohn's Patients Science didn't require that I get a placebo.

When Are Placebo Controlled Trials Ethical?

• Appropriate when: – No established standard of care.

– Clinical equipoise between placebo and the intervention.

– Temporary discomfort to patients.

– Patients are fully informed about alternative treatments outside the

trial.

• If physicians and patients who believe placebo-controlled trials are inappropriate, and choose not to participate, trials become unfeasible.

Etanercept in Crohn’s Disease

39%

9%

30%

13%

45%

20%

30%

25%

0%

10%

20%

30%

40%

50%

Response Remission Response Remission

Etanercept

Placebo

Week 4 Week 8

p = ns for all values

Sandborn, Gastroenterology 2001; 121(5): 1088-94.

Alternatives to Traditional Placebo Controlled Trials

• Add-on therapies to standard of care options (superiority).

• Non-inferiority studies against standard of care

• Cross over studies with open label treatments

Patients have Ethical Responsibilities in Trials Too

Lessons Learned from a Failed Clinical Trial of FMT (NCT02058524)

• 3 of 10 patients finished the study in its entirety

• 5 subjects were deceptive, broke rules, and/or violated research agreement – mishandling stool samples (yogurt containers)

– taking higher doses of prednisone (exclusion criteria)

– not responding the multiple phone calls from study team

– not completing study questionnaires

Kahn SA and Rubin DT. Am J Gastroenterol. 2016;111:1508-1510.

Therapeutic Misconception

• Clinic trials that offer innovative treatments that are not widely available may experience higher rates of therapeutic misconception. – Failure to recognize differences between clinical care and

participation in a clinical trial, falsely believing in a direct clinical benefit.

• Subjects agree to meet study requirements when unsuitable for them; likely to occur in desperate or vulnerable populations.

Kahn SA and Rubin DT. Am J Gastroenterol. 2016;111:1508-1510.

Summary: Ethics of Clinical Trials

• A study is ethical or not at its inception.

• Err on the side of over information and over disclosure

• Intelligent study design can contribute meaningfully to standard of care

• Blinding is not perfect, investigators can “fudge” trial entry or interpret results in ways that affect study outcome

• Reporting of results is required within a reasonable amount of time after study completion

• Patients have ethical responsibilities in trials too