Ethical Use of Human Subjects in Infectious Disease Research

Arthur O. Anderson MD

Office of Human Use and Ethics

Lecture for BCLT & BHBLS March 18, 2015

This presentation represents the views of the author. The information or content presented does not represent the official position or policy of the U.S. Army Medical Research and Materiel Command, the U.S. Army Medical Department, the Department of Defense, or the U.S. Government.

PR 15-149 (+)

Few choices in life are: Ethical, Legal & Moral

Ethical Moral Legal

Responsibility and Accountability in Research

Involves:Ethical Behavior

Morality andLawfulness

Guided by: Values , Principles and Beliefs

What Values You Choose May Influence Ethical Decisions:

Group A

1. Trust

2. Integrity

3. Courage

4. Honesty

5. Duty

6. Justice

7. Honor

Group B

1. Loyalty

2. Duty

3. Respect

4. Selfless-service

5. Honor

6. Integrity

7. Personal Courage

Values: Subjects Expect Principal Investigators to Be:

Trustworthy

Loyal

Helpful

Friendly

Courteous

Kind

Values: Researchers Hope Volunteer Subjects to Be:

Obedient

Cheerful

Thrifty

Brave

Clean

Reverent

Decisional Ethics Process:

Identify your intention(s)Determine actions to achieve intention(s)What are possible consequences of the intention or of taking specific actionsDetermine which intentions/actions give greatest benefits and result in least harmsThe context, cultural values and limits to available choices effect final determination

Applied Ethics PracticesOrganizational ethics:

Safety, Security, Equitable Compensation, Work Time, Transparency, etc.

Research ethics is individualistic: Respect for Persons, Beneficence, Distributive Justice

Clinical ethics is individualistic: Do no harm, Beneficence, Duty to Care, Evidence Based

Public Health ethics is societal not individualistic: "Public health ethics involves a systematic process to clarify,

prioritize and justify possible course of public health action based on ethical principles, values and beliefs of stakeholders, and scientific and other information” (from Powers and Faden 2006)

Public Health actions are both prudential and humanitarianPrinciple of least infringement, respects and protects individual & society/community needs, interests, rights and liberties.

Individual rights and welfare may be subordinate to those of the population if the individual’s actions endanger others. (Harm Principle)

Biosafety invented at Camp Detrick before

bioweapons developed

Biosafety invented at Camp Detrick before

bioweapons developed

A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943A.G. Wedum MD - Safety “S” Division - first division to be activated in 1943

Organizational Ethics:Organizational Ethics:

Nonpathogenic Simulants were used in Human Studies of Safety Practices

Worker safety tests were done to test air purification systems such as mechanical and electrostatic filters, air incinerators and washers (barrier)Environmental Safety by control of Ambient Air Pressures was developed and tested at Detrick (isolation)

Masks and biohazard suits were developed and tested at Detrick

WWII Human Experimentation Detrick – Occupational Safety Immunization*

Vaccination routine called “special procedures” instituted by Biological Protection Branch of S Division

Primary Objective was to protect workers Secondary Objectives:

Determine most efficacious immunization methodsDetermine effectiveness of available preparations

No existing vaccines for some agentsOnly experimental vaccines available for others

* Ltr (S), CO CD to Post Surgeon CD, 22 Jan 44, Sub: Immunization. SPCYF 400.12. In Hq CD (720.3)* Sp Rpt 15, Immunological Protection of Personnel Against B.W. Agents (Oct 46), p.2

Nuremberg War Crimes Trial

By 1947 Andrew Ivy & Leo Alexander released a list of ten conditions required for permissible medical experiments in healthy subjects became the Nuremberg Code.

The Code became the standard for ethical research with humans

23 Nazi Doctors were convicted of Murder at The Nuremberg Trials

Nuremberg Code of 1947 1. Voluntary Consent absolutely essential

2. Valid research for good of society – by no other means

3. Human studies preceded by knowledge survey & research with animal models to identify potential risks and benefits

4. Avoid unnecessary physical and mental suffering & injury

5. Prohibits research with apriori risk of death or disabling injury

6. Degree of risk never to exceed benefit or humanitarian value

7. Prepare to minimize risk of injury, disability or death

8. Investigator must have credentials appropriate to study

9. Subjects must have freedom to withdraw

10. Scientist may terminate study to reduce serious risk

What is Voluntary Consent?• This means that the person involved should have legal capacity to

give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision.

• This latter element requires that before the acceptance of an affirmative decision by the experimental subject there should be made known to him: the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; all inconveniences and hazards reasonably to be expected; and the effects upon his health or person which may possibly come from his participation in the experiment.

• The duty and responsibility for ascertaining the quality of the consent rests upon each individual who initiates, directs or engages in the experiment. It is a personal duty and responsibility which may not be delegated to another with impunity.

Wilson Memorandum of 1953The Nuremberg Code* was incorporated into the Wilson Memorandum to the Secretaries of the Army, Navy and Air Force dated 26 February 1953

* Use of its principles was promoted BEFORE any human research related to biological warfare defense were officially planned or conducted

Army Directive CS-385 issued 30 June 1953 added consent in writing, additional safeguards, a prototype aerosol study and instructions for compensating subjects for injuries resulting from participation in research

AR70-25 was Nuremberg Code Based from 1962-1990

USAMU ‘56 / USAMRIID ‘69 was established to develop the means to diagnose, treat and prevent diseases caused by biological warfare agents. Approval of the cs-385 directive for ethical operation, plans for organization of the institute, preparation of CD-22 protocols and the Dugway study preceded by 3-6 months the creation of USAMU.

The US Army Medical Unit at Fort Detrick

USAMU - USAMRIID

The station hospital was built in 1957. It was linked via walkways to support laboratories (vir, bact, clin lab, etc) and USAMU. The 8-ball is at upper left and the BL-4 suite called ”black moriah” is at upper right.

The station hospital was built in 1957. It was linked via walkways to support laboratories (vir, bact, clin lab, etc) and USAMU. The 8-ball is at upper left and the BL-4 suite called ”black moriah” is at upper right.

These wooden buildings resemble what may be found in Africa as care stations. They were safe and secure because of disinfectant sprays and partitioned space, i.e. hot, warm & cold

CD-22 & Operation Whitecoat were designed to determine:

Human vulnerability in realistic BW scenarios, i.e. outdoor aerosol delivery to human subjects

Effective prevention and treatment of BW casualties.

Determination of minimal infective doses.

Effectiveness of vaccines and drugs.

Serological responses to infections, and.

Clinical effects of various doses of infectious agents.

COL W.D. Tigertt USAMU

Community ConsultationOctober 1954 Colonel Tigertt contacted Dr. Theodore R. Flaiz of Seventh Day Adventist General Conference about seeking 1A-O SDA volunteer subjects.General Conference of SDA Church approved recruitment of drafted SDA volunteer subjects into Operation Whitecoat

Operation Whitecoat served as a model of the ethical use of human subjects in research. The three step process of informed consent - by which research subjects become familiar with the purpose of a study in order to understand the risks and potential benefits involved before agreeing to participate - was successfully implemented from the program’s inception. The soldiers were not required to participate in any of the studies, only to be present for briefings by principal investigators seeking volunteers. Two more steps occurred before subjects were asked to consent. About 20 percent of the men did not participate in any studies during their tenure at Fort Detrick.

Operation Whitecoat served as a model of the ethical use of human subjects in research. The three step process of informed consent - by which research subjects become familiar with the purpose of a study in order to understand the risks and potential benefits involved before agreeing to participate - was successfully implemented from the program’s inception. The soldiers were not required to participate in any of the studies, only to be present for briefings by principal investigators seeking volunteers. Two more steps occurred before subjects were asked to consent. About 20 percent of the men did not participate in any studies during their tenure at Fort Detrick.

Aerosol Efficacy Studies at 8 Ball

Q-fever and Tularemia were approved for these studies because safety criteria were met and cure was assured.

Q-fever and Tularemia were approved for these studies because safety criteria were met and cure was assured.

1955 Whitecoat: Aerosol Human Study in Realistic BW Scenario

Outdoor Q-fever Study - Dugway

Merlin Neff described being in the study at Dugway. "They put two of us at each station along with several monkeys and guinea pigs and mice and air sampling apparatus,“ This study satisfied the AFMPC and outdoor studies like this were never done again.

Dugway Q-fever trial men seemed to have mysteriously disappeared

Experimental Risks Minimized by Availability of Effective TreatmentExperimental Risks Minimized by Availability of Effective Treatment

"They knew that they were going to inhale a certain number of organisms, and that as soon as they became ill, they would be treated with appropriate antibiotics," said Dr. Peter Bartelloni, who was involved in the research.

"They knew that they were going to inhale a certain number of organisms, and that as soon as they became ill, they would be treated with appropriate antibiotics," said Dr. Peter Bartelloni, who was involved in the research.

The men were assured that no dose of bacteria would be fatal, and effective antibiotics would stop infection immediately after it developed.

The men were assured that no dose of bacteria would be fatal, and effective antibiotics would stop infection immediately after it developed.

Ethical Accomplishments of CD-22 & Operation Whitecoat

Effectively Used Nuremberg Code Principles in creating USAMU and in planning studies

Created Effective Informed Consent Process

Involved “Community” of the SDA Volunteers

Local and Extramural Oversight / Monitoring

Medical Accomplishments:Operation Whitecoat

Licensed vaccines were developed, including yellow fever, hepatitis, and plague. Investigational New Drug (IND) vaccines were developed, including those for Venezuelan equine encephalitis (VEE), Rift Valley fever, Q fever, and tularemia. Effective systems for biological hazard containment were developed Rift Valley Fever Virus vaccine; used in 1977 outbreak in Egypt, effected 200,000 humans (2,000 deaths) and entire sheep population.

RVF Vaccine caused Peace to break out in the middle east

Therefore, a little known benefit that Operation Whitecoat Volunteers provided was to enable peace between Egypt and Israel to “break out” because obtaining RVF Vaccine was an important bargaining chip to both parties.

Emissaries from Egypt and Israel requested RVFV as Sadat & Begin met at Camp David. N Meyers - Nature 1986 Jan 9; v319(6049):

p91

Kefauver-Harris Drug Amendments passed in 1962 to ensure drug efficacy and greater drug safety. For the first time, manufacturers of drugs are required to show proof to the FDA of the efficacy of their products before they may be approved for marketing.

FDA Milestone

1962 Amendments to the FD&C Act requiring proof of efficacy of drugs and vaccines created a moral dilemma:

Risk killing subjects in a valid clinical trial, versus

Withholding potentially life saving drugs or vaccines because they lacked substantial evidence of human clinical efficacy.

Moral Dilemma: Comply with FDA law vs Intent to Benefit in BW EmergencyMoral Dilemma: Comply with FDA law

vs Intent to Benefit in BW Emergency

USPHS Tuskegee Syphilis Study Led To New Regulations:

National Research Act of 1974 requiring new regulations for protection of human subjects

Informed consent requirements Review of research by IRBs

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

1979: National Commission wrote the “Belmont report” - AKA - ”The Common Rule” NIH uses 45 CFR 46 | DoD uses 32 CFR 219

Common Rule Principles 1979

BENEFICENCE JUSTICE

RESPECT FOR PERSONS

Privacy & Confidentiality

Protection of subjects (especially vulnerable

populations)

Informed consentSurrogate consent

Assent

Risk/Benefit AnalysisExperimental DesignQualifications of PI

Subject selectionInclusion/exclusion

Recruitment

J. Cooper, Albany Medical Center

USAMRIID Research Influenced by News Events and World Affairs“Cold War” imperatives continued until 1989, and the fall of the Berlin Wall but new threats on the horizon. 1993+ Virology Research Spurred by Emerging Diseases and Global Travel Disease Transmission Risks. 1995 Aum Shinrikyo signaled that Bioterrorism was Emerging, prompting expansion development of Rapid Diagnostics, i.e. PCR & other Advanced Technologies. 1997 Global Disease Surveillance & Response Planning raised concerns about ability to comply with FDA Re: Use of IND/IDE products in pipeline for emergency use.MRVS Program Tested Safety of WRAIR & USAMRIID Vaccines & Drugs Through 2001Post September 11, 2001 Anthrax Letters and Bioterrorism fears caused U.S. to increase Biodefense infrastructure

Ethical Dichotomy Intrinsic to National Biodefense Program:

Emergency circumstances may affect outcomes of ethical analyses by weighting different values, thus favoring mitigating actions over caution

Choices:I. Respect the rights and welfare of subjects who participate

in research designed to discover, validate and gain FDA marketing approval for products to be used in prevention and treatment of possible bioterrorism casualties.

Versus: II. Urgent need to use unapproved products reasonably

thought to be beneficial for protection from - or immediate treatment of bioterrorism when there is an emergency and no approved alternatives are available.

Ethical Analysis vs Rules & Laws HHS Common Rule Regulates Research based on Ethical Principles but applied as

RulesFDA Regulates Product FD&CA Law & FDA regulates development,

labeling, marketing and use of drugs, biologics & devices

FDA defines use of product labeled IND / IDE as Research irrespective of intended use

Nuremberg Code provides principles that may be applied in Ethical Analyses for Biodefense Research

Project BioShield CDC, HHS & DoD may use HHS Project BioShield as specified in the following legislation:

Passed: H.R. 2122 Project Bioshield Act - July 16 2003 Passed: S. 15 Project BioShield Act - May 19 2004 President Signed : Public Law No: 108-276 July 21 2004 Presented: H.R. 4258 Rapid Pathogen Identification to

Delivery of Cures Act - May 3, 2004 These legislative acts may resolve the dilemma associated with the need for widespread use of FDA-unapproved products in for national biodefense or war hazards when it is unethical to do FDA-mandated human clinical efficacy studies. 21 CFR Part 314.600 - .650Additional legislation may be necessary to further define how these new laws will operate through existing agencies without damaging the fabric of regulation protecting the public from unsafe and ineffective drugs.Federal Food Drug and Cosmetic Act, section 564 (EUA)

USAMRIID Research on Medical Countermeasures against Ebola

An update of the current situation Why the current outbreak got so big so quickly?How is Ebola virus transmitted?

Is the virus transmitted by aerosol? Droplets of body fluids not Small Particle Aerosol Contact with Skin & mucus membranes & with

contaminated surfaces of objectsHow do we stop the virus from spreading?Do we have vaccines and therapeutics against Ebola virus? Do we know the reservoir(s) for Ebola virus?Conclusions

Since the discovery of Ebola in 1976 until December 2013: 23 outbreaks 2388 human cases and 1590 deaths

As of 12 March 2015, Guinea, Liberia, Sierra Leone & 7 other countries have reported over 24,544 cases and 10,111 deaths

→ This is the Largest Ebola Virus Disease outbreak ever recorded

Ebola Outbreak History

Country Year Number of cases

Number of deaths

Cote d’Ivoire 1994 1 0

Uganda 2012 7 4

Gabon 1994 52 31

DRC 2007 264 187

Uganda 2000 425 224

A few examples of previous EVD outbreaks

Barkedu is a very tightknit community. (from NPR report)

If a neighbor gets sick, you help him/her. If a highly respected person gets sick, everyone comes to help.

Barkedu’s first Ebola case was Laiye Barwor, a favorite son of the village. When he got sick in early June, the whole town took notice.

Unaware of Ebola, his family brought him to traditional healers - he died during the journey.

At his funeral, more than 30 people helped wash and prepare his body for burial – (Important to Muslims)

All people who touched him came down with Ebola. From that one funeral, Ebola spread like wildfire

Barkedu

From NY Times Report

Why did the current outbreak got so big so quickly?This was the first Ebola outbreak in West Africa:

Lack of local knowledge of how to avoid Ebola Virus Lack of HCW experience with care vs contamination Limited manpower capacity for rapid response

High level of exposure in communities Through household care by family members (droplets) Traditional burial practices (touching, kissing, washing) Fear & Panic led to resistance to response measures Travel of patients / contacts to neighbouring communities

spread infection and impacted contact tracing

Lack of sufficient commitment of resources to the epidemic in rural areas AND in large cities

Epidemiological (human case data)

Direct contact with bodily fluids

Respiratory droplets

Blood/re-used needles

Animal Experimental Methods of Infection • Oral• Conjunctival• Respiratory• Intramuscular• Intraperitoneal• Submucosal

How is Ebola virus transmitted?

Ebola virus is transmitted by touch or body fluid droplets

Ebola Viral Antigen in NHP Lip (L), Trachea (M) and Bowel (R). In each image the virus is close to or on the epithelial surface.

How do we stop the virus from spreading?

How do we stop spread of Ebola?

Bleach and other anti-infectives, steam sterilization, incineration of waste

Quickly Identify infected individuals & contacts

Liberty Restriction, Isolation / quarantine

Use of vaccines and therapeutics

Educating the public – engage community

Safe, Respectful Burial Practices

Enhance health care standard

Identifying the source (reservoir)

Anti-EBOV Therapeutic Portfolio Development

3 Synthetic Abs

Polymerase Inhib.

Polymerase Inhib.

Small interfering RNA

Antisense PM-oligomers

Nucleoside analog

Anti-EBOV Vaccine Portfolio Development

ConclusionsEbola virus is extremely infectious & spreads rapidly through personal contact and fluids

Fast multifaceted response needed to contain the epidemic: community engagement, risk education, patient isolation, contact tracing, quarantines

Protection of healthcare workers & staff with PPE

Public Health Ethics deliberations, community collaboration and epidemic mitigation planning need to occur long BEFORE the next outbreak

Protocols for IND Vaccines and Therapeutics must be prepared, reviewed and ready BEFORE needed

There will be other outbreaks.

USAMRIIDUSAMRIID

Over the past 60 years since the start of Operation Whitecoat, the U.S. Army Medical Research Institute of Infectious Diseases has grown considerably from what it was as the U.S. Army Medical Unit, yet It continues to conduct basic and applied research on biological threats resulting in medical solutions to protect military service members.

The present building was planned by COL Dan Crozier, and is named in his honor.

Over the past 60 years since the start of Operation Whitecoat, the U.S. Army Medical Research Institute of Infectious Diseases has grown considerably from what it was as the U.S. Army Medical Unit, yet It continues to conduct basic and applied research on biological threats resulting in medical solutions to protect military service members.

The present building was planned by COL Dan Crozier, and is named in his honor.

USAMRIID Ebola Info Online

USAMRIID Targets Ebola, Other Infectious Diseases http://www.defense.gov/news/newsarticle.aspx?id=123530 http://www.dvidshub.net/video/371474/us-military-leads-way-ebola-containment#.

VIBZ0WOa9bw http://www.dvidshub.net/video/371474/us-military-leads-way-ebola-containment#.

VIBZ0WOa9bw

USAMRIID Has Years of Ebola Drug Expertise http://www.defense.gov/news/newsarticle.aspx?id=123527

USAMRIID Contributes to Vaccine Development Effort http://www.defense.gov/news/newsarticle.aspx?id=123515 http://www.dvidshub.net/video/371229/army-scientists-make-ebola-vaccine-adva

nces#.VIBZOmOa9bw

USAMRIID Develops Ebola Diagnostics http://www.defense.gov/news/newsarticle.aspx?id=123498

Arthur O. Anderson MDDirector, Office of Human Use and Ethics

US Army Medical Research Institute of Infectious Diseases 

Arthur O. Anderson MDDirector, Office of Human Use and Ethics

US Army Medical Research Institute of Infectious Diseases