Ethics: Part 1, Human Testing Biotechnology Law and Regulation CUSCI, Biol 503, Spring 2008 K. Pessin

Ethics: Human Testing Objective Understand human testing involves special ethical considerations Understand modern interpretations of permissible human testing Understand ethical considerations involving vulnerable populations who may be used in medical tests

Objective

Understand human testing involves special ethical considerations

Understand modern interpretations of permissible human testing

Understand ethical considerations involving vulnerable populations who may be used in medical tests

Ethics: Human Testing Historical Nazis and the Nuremburg Code Post WWII leading to modern regulations Selected issue: Consent in vulnerable populations Prisoners Developing countries Pfizer in Nigeria First-in-man

Historical

Nazis and the Nuremburg Code

Post WWII leading to modern regulations

Selected issue: Consent in vulnerable populations

Prisoners

Developing countries

Pfizer in Nigeria

First-in-man

Ethics: Human Testing Nuremberg Code: Permissible Medical Testing Informed Consent Experiment should yield valid results Pre-clinical animal studies No disabling injury Avoid suffering and injury Risk balanced with benefits Qualified investigators Subject free to stop at any time Investigator must be prepared to stop

Nuremberg Code: Permissible Medical Testing

Informed Consent

Experiment should yield valid results

Pre-clinical animal studies

No disabling injury

Avoid suffering and injury

Risk balanced with benefits

Qualified investigators

Subject free to stop at any time

Investigator must be prepared to stop

Ethics: Human Testing Field Trip

Ethics: Human Testing Chief U.S. Counsel Justice Robert Jackson delivers the prosecution's opening statement at the International Military Tribunal. Nuremberg, Germany, November 21, 1945.

Ethics: Human Testing http://nuremberg.law.harvard.edu/php/docs_swi.php?DI=1&text=doc_anal Nuremberg Doctor’s Trial, Prosecution's Opening Statement (Dec. 9, 1946)

Ethics: Human Testing Defendants seated under guard. American judges. The prosecution team

Ethics: Human Testing Vladislava Karolewska, a victim of medical experiments, who appeared as a prosecution witness Defendant Dr.. Gerhard Rose, advised on high altitude and freezing experiments. Herta Oberheuser, Nazi physician on trial

Ethics: Human Testing Experiments in the Indictment A) High-Altitude Experiments B) Freezing Experiments C) Malaria Experiments D) Lost (Mustard) Gas Experiments E) Sulfanilamide Experiments F) Bone, Muscle, and Nerve Regeneration and Bone Transplantation Experiments G) Sea-Water Experiments H) Epidemic Jaundice Experiments I) Sterilization Experiments J) Spotted Fever (Fleckfieber) Experiments K) Experiments with Poison L) Incendiary Bomb Experiments

Experiments in the Indictment

A) High-Altitude Experiments B) Freezing Experiments C) Malaria Experiments D) Lost (Mustard) Gas Experiments E) Sulfanilamide Experiments F) Bone, Muscle, and Nerve Regeneration and Bone Transplantation Experiments G) Sea-Water Experiments H) Epidemic Jaundice Experiments I) Sterilization Experiments J) Spotted Fever (Fleckfieber) Experiments K) Experiments with Poison L) Incendiary Bomb Experiments

Ethics: Human Testing http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C THE NUREMBERG CODE Permissible Medical Experiments The great weight of the evidence before us is to the effect that certain types of medical experiments on human beings, when kept within reasonably well-defined bounds, conform to the ethics of the medical profession generally. The protagonists of the practice of human experimentation justify their views on the basis that such experiments yield results for the good of society that are unprocurable by other methods or means of study. All agree, however, that certain basic principles must be observed in order to satisfy moral, ethical and legal concepts:

Ethics: Human Testing Nuremberg Doctor’s Trial, Prosecution's Opening Statement (Dec. 9, 1946) http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C 1. The voluntary consent of the human subject is absolutely essential .

Ethics: Human Testing 1. The voluntary consent of the human subject is absolutely essential . This means that the person involved should have . . . Legal capacity to give consent; No “force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion”; “ Sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision;” Knowledge of the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted; http://www.ushmm.org/research/doctors/Nuremberg_Code.htm

1. The voluntary consent of the human subject is absolutely essential .

This means that the person involved should have . . .

Legal capacity to give consent;

No “force, fraud, deceit, duress, over-reaching, or other ulterior form of constraint or coercion”;

“ Sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision;”

Knowledge of the nature, duration, and purpose of the experiment; the method and means by which it is to be conducted;

Ethics: Human Testing Nuremberg Doctor’s Trial, Prosecution's Opening Statement (Dec. 9, 1946) http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C 2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature. Prosecution Exhibit, poison bullet

Ethics: Human Testing Nuremberg Doctor’s Trial, Prosecution's Opening Statement (Dec. 9, 1946) http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C 3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment. “ Potable sea water” experiment performed on concentration camp prisoner

Ethics: Human Testing http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C Nuremberg Doctor’s Trial, Prosecution's Opening Statement (Dec. 9, 1946) 4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.

Ethics: Human Testing http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C 5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.

Ethics: Human Testing http://nuremberg.law.harvard.edu/php/pflip.php?caseid=HLSL_NMT01&docnum=565&numpages=62&startpage=1&title=Opening+Statement+for+the+United+States+of+America.&color_setting=C 6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment. Freezing experiments .

Ethics: Human Testing 7 . Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death. Bone regeneration “experiment”

7 . Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.

Ethics: Human Testing 8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.

Ethics: Human Testing 9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible. Compression chamber

9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.

Ethics: Human Testing 10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probably cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject. Exhibit in Nuremberg trial: Phosphorous experiment injuryhttp://www.law.umkc.edu/faculty/projects/ftrials/nuremberg/docphos.jpg

10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probably cause to believe, in the exercise of the good faith, superior skill and careful judgment required of him that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Ethics: Human Testing . . .Obviously all of these experiments involving brutalities, tortures, disabling injury, and death were performed in complete disregard of international conventions, the laws and customs of war, the general principles of criminal law as derived from the criminal laws of all civilized nations. . . . Manifestly human experiments under such conditions are contrary to "the principles of the law of nations as they result from the usages established among civilized peoples, from the laws of humanity, and from the dictates of public conscience." THE NUREMBERG CODE [from Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10. Nuremberg, October 1946–April 1949. Washington, D.C.: U.S. G.P.O, 1949–1953.]

. . .Obviously all of these experiments involving brutalities, tortures, disabling injury, and death were performed in complete disregard of international conventions, the laws and customs of war, the general principles of criminal law as derived from the criminal laws of all civilized nations. . . . Manifestly human experiments under such conditions are contrary to "the principles of the law of nations as they result from the usages established among civilized peoples, from the laws of humanity, and from the dictates of public conscience."

Ethics: Human Testing - Reference Declaration of Helinski (1964, … 2000) http://www.wma.net/e/policy/b3.htm World Medical Association Formed after WWII Human Rights, including medical doctors who are witnesses to torture, other abuses http://www.wma.net/e/humanrights/indistress_cases.htm International Standard Recognized in FDA regulation HHS IRB Guidebook http://www.hhs.gov/ohrp/irb/irb_appendices.htm#j5

Declaration of Helinski (1964, … 2000)

http://www.wma.net/e/policy/b3.htm

World Medical Association

Formed after WWII

Human Rights, including medical doctors who are witnesses to torture, other abuses http://www.wma.net/e/humanrights/indistress_cases.htm

International Standard

Recognized in FDA regulation

Ethics: Human Testing CALIFORNIA HEALTH AND SAFETY CODE SECTION 24170-24179.5 (CALIFORNIA EXPERIMENTAL SUBJECT’S BILL OF RIGHTS) . . . The Legislature further finds and declares that: (a) The Nuremberg Code of Ethics in Medical Research was developed after the trial of Nazi war criminals for unethical use of persons in medical experiments; subsequently, the Declaration of Helsinki additionally established recommendations guiding doctors in experimentation involving human subjects. (b) Neither the Nuremberg Code nor the Declaration of Helsinki are codified under law and are, therefore, unenforceable. (c) It is necessary that medical experimentation be done in such a way as to protect the rights of the human subjects involved. (d) There is, and will continue to be, a growing need for protection for citizens of the state from unauthorized, needless, hazardous, or negligently performed medical experiments on human beings. It is, therefore, the intent of the Legislature, in the enacting of this chapter, to provide minimum statutory protection for the citizens of this state with regard to human experimentation and to provide penalties for those who violate such provisions. http://www.leginfo.ca.gov/cgi-bin/displaycode?section=hsc&group=24001-25000&file=24170-24179.5

CALIFORNIA HEALTH AND SAFETY CODE SECTION 24170-24179.5 (CALIFORNIA EXPERIMENTAL SUBJECT’S BILL OF RIGHTS)

. . . The Legislature further finds and declares that:

(a) The Nuremberg Code of Ethics in Medical Research was developed after the trial of Nazi war criminals for unethical use of persons in medical experiments; subsequently, the Declaration of Helsinki additionally established recommendations guiding doctors in experimentation involving human subjects.

(b) Neither the Nuremberg Code nor the Declaration of Helsinki are codified under law and are, therefore, unenforceable.

(c) It is necessary that medical experimentation be done in such a way as to protect the rights of the human subjects involved.

(d) There is, and will continue to be, a growing need for protection for citizens of the state from unauthorized, needless, hazardous, or negligently performed medical experiments on human beings. It is, therefore, the intent of the Legislature, in the enacting of this chapter, to provide minimum statutory protection for the citizens of this state with regard to human experimentation and to provide penalties for those who violate such provisions.

http://www.leginfo.ca.gov/cgi-bin/displaycode?section=hsc&group=24001-25000&file=24170-24179.5

Ethics: Human Testing 24172. As used in the chapter, "experimental subject's bill of rights," means a list of the rights of a subject in a medical experiment, written in a language in which the subject is fluent. Except as otherwise provided in Section 24175, this list shall include, but not be limited to the subject's right to: (a) Be informed of the nature and purpose of the experiment. (b) Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be utilized. (c) Be given a description of any attendant discomforts and risks reasonably to be expected from the experiment. (d) Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable. (e) Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be advantageous to the subject, and their relative risks and benefits. (f) Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise. (g) Be given an opportunity to ask any questions concerning the experiment or the procedures involved. (h) Be instructed that consent to participate in the medical experiment may be withdrawn at any time and the subject may discontinue participation in the medical experiment without prejudice. (i) Be given a copy of the signed and dated written consent form as provided for by Section 24173 or 24178. (j) Be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on the subject's decision . http://www.leginfo.ca.gov/cgi-bin/displaycode?section=hsc&group=24001-25000&file=24170-24179.5

24172. As used in the chapter, "experimental subject's bill of rights," means a list of the rights of a subject in a medical experiment, written in a language in which the subject is fluent. Except as otherwise provided in Section 24175, this list shall include, but not be limited to the subject's right to:

(a) Be informed of the nature and purpose of the experiment.

(b) Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be utilized.

(c) Be given a description of any attendant discomforts and risks reasonably to be expected from the experiment.

(d) Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable.

(e) Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be advantageous to the subject, and their relative risks and benefits.

(f) Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise.

(g) Be given an opportunity to ask any questions concerning the experiment or the procedures involved.

(h) Be instructed that consent to participate in the medical experiment may be withdrawn at any time and the subject may discontinue participation in the medical experiment without prejudice.

(i) Be given a copy of the signed and dated written consent form as provided for by Section 24173 or 24178.

(j) Be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on the subject's decision .

http://www.leginfo.ca.gov/cgi-bin/displaycode?section=hsc&group=24001-25000&file=24170-24179.5

Ethics: Human Testing Intentional human pesticide dosing ethics challenge No: No benefit to the individual by being dosed with a pesticide Yes: Non-harmful doses are administered, and we can obtain data useful for the better good -- people who may have already been exposed http://darwin.nap.edu/books/0309091721/html/R1.html Quiz seal

Intentional human pesticide dosing ethics challenge

No: No benefit to the individual by being dosed with a pesticide

Yes: Non-harmful doses are administered, and we can obtain data useful for the better good -- people who may have already been exposed

Ethics: Human Testing Summary: The Nuremberg Code Nazi doctors on trial in Nuremberg performed horrific atrocities on concentration camp prisoners (and others) The Nuremberg Code was written to spell out in no uncertain terms permissible medical experiments The Nuremberg Code is the basis for international laws and regulations for permissible human medical experimentation

Summary: The Nuremberg Code

Nazi doctors on trial in Nuremberg performed horrific atrocities on concentration camp prisoners (and others)

The Nuremberg Code was written to spell out in no uncertain terms permissible medical experiments

The Nuremberg Code is the basis for international laws and regulations for permissible human medical experimentation

Ethics: Human Testing Development of current ethical regulations for human clinical trials Historical US lapses (Tuskegee) Cold War Era ’70’s developments Federal Regulations Current Issue Commercial IRB bias

Development of current ethical regulations for human clinical trials

Historical US lapses (Tuskegee)

Cold War Era

’70’s developments

Federal Regulations

Current Issue

Commercial IRB bias

Ethics: Human Testing Post WWII – Post Nuremburg, US Medical Community Reaction to Nuremberg Code: “ It’s a good code for barbarians, but unnecessary for civilized medical professionals.” US ethical lapses justified on the basis of “fear of communism” Led to current regulations for Institutional Review Board (“IRB”) review

Post WWII –

Post Nuremburg, US Medical Community Reaction to Nuremberg Code:

“ It’s a good code for barbarians, but unnecessary for civilized medical professionals.”

US ethical lapses justified on the basis of “fear of communism”

Led to current regulations for Institutional Review Board (“IRB”) review

Ethics: Human Testing Non-consensual human testing Tuskegee Syphilis study 1920’s-1960’s Untreated black males with syphilis, even after treatment was available

Non-consensual human testing

Tuskegee Syphilis study

1920’s-1960’s

Untreated black males with syphilis, even after treatment was available

Ethics: Human Testing Post WWII: The Atomic Age Fear of Communists Lack of any kind of consent Environmental radiation releases Prisoner trials Failure to inform at all – e.g., LSD

Post WWII: The Atomic Age

Fear of Communists

Lack of any kind of consent

Environmental radiation releases

Prisoner trials

Failure to inform at all – e.g., LSD

Ethics: Human Testing M.I.T. “Ferdinand School” tests: 1940’s-’50’s “Mentally retarded” children fed radioactive breakfast treats Parents not informed Children asked for “special treat” (coercion) http:// www.eh.doe.gov/ohre/roadmap/achre/index.html Final Report of the Advisory Committee on Human Radiation Experiments DOE Advisory Committee On Human Radiation Experiments Reports

M.I.T. “Ferdinand School” tests:

1940’s-’50’s “Mentally retarded” children fed radioactive breakfast treats

Parents not informed

Children asked for “special treat” (coercion)

http:// www.eh.doe.gov/ohre/roadmap/achre/index.html Final Report of the Advisory Committee on Human Radiation Experiments DOE Advisory Committee On Human Radiation Experiments Reports

Ethics: Human Testing http://www.archives.gov/exhibits/nixon-met-elvis/index.html The '70's

Ethics: Human Testing http://ian.onepeople.org/files/HumanDrug.pdf Statement of Dr. Sidney Gottleib, M.D., in 1977 Senate hearing, testifying with immunity from prosecution, page 206 of hearings conducted September 21 and 22 , 1977. Secret LSD tests by CIA

Ethics: Human Testing 1978-79: Laws to protect human subjects Institutional review boards (“IRB’s”) http://ohsr.od.nih.gov/guidelines/belmont.html#goc1 "IRB" = Institutional Review Board

Ethics: Human Testing http://www.wirb.com/images/WIRB%20Workflow%20-%20General.gif

Ethics: Human Testing http://www.fda.gov/foi/warning_letters/s6882c.pdf Even IRBs get questioned

Ethics: Human Testing For-profit IRB handles over half of new FDA submissions.

Ethics: Human Testing Allegation: "IRB was negligent in allowing placebo control arm."

Ethics: Human Testing Summary Post WWII US human testing did not follow Nuremberg code Justified by fear of Communism Led to creation of regulations Institutional Review Board (“IRB”) Even IRB’s may need oversight Next: Vulnerable populations

Summary

Post WWII US human testing did not follow Nuremberg code

Justified by fear of Communism

Led to creation of regulations

Institutional Review Board (“IRB”)

Even IRB’s may need oversight

Next: Vulnerable populations

Ethics: Human Testing In depth: Consent Among Vulnerable Populations U.S. Prison Population Clinical trials in developing countries (India) Nigeria vs. Pfizer First-in-man trials

In depth: Consent Among Vulnerable Populations

U.S. Prison Population

Clinical trials in developing countries (India)

Nigeria vs. Pfizer

First-in-man trials

Ethics: Human Testing Consent Voluntary Not coerced Vulnerable populations Informed Risks disclosed Risks understood

Consent

Voluntary

Not coerced

Vulnerable populations

Informed

Risks disclosed

Risks understood

Ethics: Human Testing Belmont Report – Vulnerable populations are especially protected Pregnant women/fetuses Prisoners Children Mentally incapacitated Economically disadvantaged Educationally disadvantaged Elderly Patients/Students/Employees

Belmont Report – Vulnerable populations are especially protected

Pregnant women/fetuses

Prisoners

Children

Mentally incapacitated

Economically disadvantaged

Educationally disadvantaged

Elderly

Patients/Students/Employees

Ethics: Human Testing 2006: National Academy of Sciences: Prisoner Testing OK With New Guidelines Benefits drug co.’s: Shortage of test subjects 7,000,000 – incarcerated, parole, work release, etc. Benefits society: shift medical cost to industry Cost likely to increase: “Graying”, mental illness, HIV, HepC, addiction Prison medical system is inadequate http://darwin.nap.edu/books/0309101190/html/47.html

2006: National Academy of Sciences: Prisoner Testing OK With New Guidelines

Benefits drug co.’s: Shortage of test subjects

7,000,000 – incarcerated, parole, work release, etc.

Benefits society: shift medical cost to industry

Cost likely to increase: “Graying”, mental illness, HIV, HepC, addiction

Prison medical system is inadequate

Ethics: Human Testing National Academy of Sciences: Prisoner Testing OK Expand the definition of prisoner Ensure universal, consistent, ethical protection Shift from a category-based to a risk-benefit approach Update the ethical framework to include collaborative responsibility http://darwin.nap.edu/books/0309101190/html/R2.html

National Academy of Sciences: Prisoner Testing OK

Expand the definition of prisoner

Ensure universal, consistent, ethical protection

Shift from a category-based to a risk-benefit approach

Update the ethical framework to include collaborative responsibility

Ethics: Human Testing http://www.ccr-ny.org/v2/legal/justice/docs/jailhouselawyershandbook.pdf

Ethics: Human Testing http://www.venturacountystar.com/news/2008/dec/30/sacred-cow-prisons-wasting-taxpayers-money/

Ethics: Human Testing Is informed, voluntary consent possible with a prison population? Uneducated population, many mentally ill Clinical trial pays better than prison jobs – coercion? “ Prison ethics” bribery, monitoring http://video.on.nytimes.com/ifr_main.jsp?nsid=a2079ba3e:10d05391ec2:10ec&fr_story=350ed2566d929c050153e63a6547e1342538707b&st=1155440197765&mp=FLV&cpf=false&fr=080806_045041_332ced11x10cef73755dxw4481&rdm=318847.8831147018

Is informed, voluntary consent possible with a prison population?

Uneducated population, many mentally ill

Clinical trial pays better than prison jobs – coercion?

“ Prison ethics” bribery, monitoring

Ethics: Human Testing http://www.cnn.com/2006/LAW/10/12/robber.retirement.ap/index.html If Medicare runs out before I die, I’ll just commit a crime and go to jail – they have great medical benefits!

Quiz Who’s more vulnerable, patients or prisoners? Hypothetical conversation Oncologist: You’re going to die anyway, why not just try this new test drug? Cancer patient: What other options do I have? Oncologist: You could do nothing, or try things we know don’t work and may make your quality of life worse. Next: Consent or coercon? Quiz seal

Who’s more vulnerable, patients or prisoners?

Hypothetical conversation

Oncologist: You’re going to die anyway, why not just try this new test drug?

Cancer patient: What other options do I have?

Oncologist: You could do nothing, or try things we know don’t work and may make your quality of life worse.

Next: Consent or coercon?

Ethics: Human Testing Panama City 1905 Fumigation brigades eradicating the mosquitoes Field Trip Clinical trials in developing nations

Ethics: Human Testing Panama City 1905 Yellow Fever Quarantine Station Dr. Walter Reed: Is yellow fever transmitted by humans or by mosquitos?

Ethics: Human Testing http://etext.virginia.edu/healthsci/reed/commission.html Informed consent: Yellow fever experiments 1900 $100 US gold for participating, $200 more if you get yellow fever

Ethics: Human Testing http://ocw.jhsph.edu/courses/EthicsHumanSubjectResearch/PDFs/Coercion.pdf

Ethics: Human Testing http://www.washingtonpost.com/wp-dyn/content/article/2007/02/18/AR2007021800458_pf.html

Ethics: Human Testing http://abcnews.go.com/Health/AIDS/Story?id=4496620&page=1

Ethics: Human Testing Field Trip

Ethics: Human Testing Huge patient population, “treatment naïve” Specialty hospitals with state of the art facilities 700,000 hospital beds and 221 medical colleges Skilled, English speaking investigators Apollo Hospital, Delhi http://www.planethospital.com/special_packages.php

Huge patient population, “treatment naïve”

Specialty hospitals with state of the art facilities

700,000 hospital beds and 221 medical colleges

Skilled, English speaking investigators

Ethics: Human Testing Outsourcing Clinical Trials

Ethics: Human Testing http://wired.com/news/medtech/0,1286,69595,00.html?tw=wn_tophead_1

Ethics: Human Testing http://www.pharmabiz.com/article/detnews.asp?articleid=27444&sectionid=46 Clinical Trials - Commerce versus Ethics Wednesday, May 04, 2005 08:00 IST Bindu Dey and Payal Dey, PharmBiz Outsourcing Clinical Trials Does India Need and ED drug?

Ethics: Human Testing http://www.financialexpress.com/fe_archive_full_story.php?content_id=85704 3/20/05

Ethics: Human Testing Developing country issues: Coercive consent with money “ Offering $100 may be undue enticement; they may not even realize that they are being coerced”. . . Exploitative – drugs tested are for industrial nations, not developing world (e.g., Cialis®) Not enough independent ethical oversight IRB’s frequently underfunded, no clear understanding of study or ethics requirements Cultural Consent Issues: Women need husband’s consent; rural areas require community consent; individuals overly trusting of doctors

Developing country issues:

Coercive consent with money

“ Offering $100 may be undue enticement; they may not even realize that they are being coerced”. . .

Exploitative – drugs tested are for industrial nations, not developing world (e.g., Cialis®)

Not enough independent ethical oversight

IRB’s frequently underfunded, no clear understanding of study or ethics requirements

Cultural Consent Issues: Women need husband’s consent; rural areas require community consent; individuals overly trusting of doctors

Ethics: Human Testing Kalo Hospital, Nigeria – Pfizer clinical trial for antibiotic 1996 http://www.washingtonpost.com/wp-dyn/world/issues/bodyhunters/ Field Trip Humanitarian free drug or exploitive human testing?

Ethics: Human Testing Kalo Hospital, Nigeria – Pfizer clinical trial for antibiotic 1996 http://www.washingtonpost.com/wp-dyn/world/issues/bodyhunters/

Ethics: Human Testing http://news.bbc.co.uk/2/hi/africa/6721771.stm

Ethics: Human Testing Abdullahi v. Pfizer, Inc., No. 02-9223 (2d Cir. 10/08/2003) Nos. 02-9223 (L), 02-9303 (XAP) October 8, 2003 (unpublished district court decision quoted below) Case dismissed at the appellate level for lack of jurisdiction. “ . . . The central events at issue in this lawsuit occurred in 1996, not long after epidemics of bacterial meningitis, measles and cholera broke out in Kano, Nigeria. Pfizer established a treatment center at the Infectious Disease Hospital in Kano to treat victims of the meningitis epidemic. Plaintiffs allege that Pfizer, instead of using safe and effective bacterial meningitis treatments, used the epidemic as an opportunity to conduct biomedical research experiments on Nigerian children . . . “ [The basis for ] . . . jurisdiction in the District Court was 28 U.S.C. § 1350, the Alien Tort Claims Act ("ATCA"), because Pfizer purportedly violated the Nuremberg Code, the Declaration of Helsinki, article 7 of the International Covenant on Civil and Political Rights, FDA regulations and other norms of international law . . .” N.Y. Judge to Nigeria: Case dismissed! Sue Pfizer in Nigeria, not the U.S.

Abdullahi v. Pfizer, Inc., No. 02-9223 (2d Cir. 10/08/2003) Nos. 02-9223 (L), 02-9303 (XAP) October 8, 2003 (unpublished district court decision quoted below)

Case dismissed at the appellate level for lack of jurisdiction.

“ . . . The central events at issue in this lawsuit occurred in 1996, not long after epidemics of bacterial meningitis, measles and cholera broke out in Kano, Nigeria. Pfizer established a treatment center at the Infectious Disease Hospital in Kano to treat victims of the meningitis epidemic. Plaintiffs allege that Pfizer, instead of using safe and effective bacterial meningitis treatments, used the epidemic as an opportunity to conduct biomedical research experiments on Nigerian children . . .

“ [The basis for ] . . . jurisdiction in the District Court was 28 U.S.C. § 1350, the Alien Tort Claims Act ("ATCA"), because Pfizer purportedly violated the Nuremberg Code, the Declaration of Helsinki, article 7 of the International Covenant on Civil and Political Rights, FDA regulations and other norms of international law . . .”

Ethics: Human Testing http://money.cnn.com/2006/05/06/news/companies/pfizer_reut0506/index.htm

Ethics: Human Testing

Ethics: Human Testing http://www.pharmalot.com/2008/12/will-pfizer-pay-fictitious-trovan-victims-in-nigeria/

Ethics: Human Testing Summary of selected ethical issues for clinical trials in developing countries Does the country need the drug? Is patient consent available? Vulnerable population? Skilled professionals and access to site monitors? Next: First-in-man

Summary of selected ethical issues for clinical trials in developing countries

Does the country need the drug?

Is patient consent available? Vulnerable population?

Skilled professionals and access to site monitors?

Next: First-in-man

Ethics: Human Testing http://www.dailymail.co.uk/pages/live/articles/news/news.html?in_article_id=418792&in_page_id=1770 First in Man. . .

Ethics: Human Testing Navneet Modi was one of six subjects who nearly died in the trial. http://www.nytimes.com/2006/08/03/world/europe/03britain.html?pagewanted=1&ref=health TeGenero, “First-in-man”

Ethics: Human Testing

Ethics: Human Testing Clinical trials where mode of action is novel (“first-in-man”) Ethically requires heightened scientific research Informed consent and duty to warn about and prepare for possible catastrophic outcomes

Clinical trials where mode of action is novel (“first-in-man”)

Ethically requires heightened scientific research

Informed consent and duty to warn about and prepare for possible catastrophic outcomes

Ethics: Human Testing “Access, Compassion, Care, and Ethics for Seriously Ill Patients Act” (the “ACCESS Act”) Access to experimental drugs for critically ill patients; policy for “compassionate” use Accelerated “conditional” FDA approval Manufacturer immunity from lawsuits Quiz seal Should desperately ill patients be given experimental drugs?

“Access, Compassion, Care, and Ethics for Seriously Ill Patients Act” (the “ACCESS Act”)

Access to experimental drugs for critically ill patients; policy for “compassionate” use

Accelerated “conditional” FDA approval

Manufacturer immunity from lawsuits

Ethics: Human Testing Nuremberg Code “permissible medical testing” Consent must be informed and voluntary Institutional Review Boards and regulations Vulnerable populations Prisoners Developing countries Third world First-in-man

Nuremberg Code “permissible medical testing”

Consent must be informed and voluntary

Institutional Review Boards and regulations

Vulnerable populations

Prisoners

Developing countries

Third world

First-in-man

Ethics: Human Testing Human Subjects Research and IRBs Ethics Codes and Standards Regulations, Policies and Guidance IRB Resources Human Subjects Research Tutorials and Case Studies Responsible Conduct of Research

Human Subjects Research and IRBs

Ethics Codes and Standards Regulations, Policies and Guidance IRB Resources Human Subjects Research Tutorials and Case Studies Responsible Conduct of Research

Ethics: Human Testing Institutional Review Board (IRB) Resources The IRB Forum - A forum sponsored by the Medical College of Wisconsin that promotes the exchange of ethical, regulatory, and policy concerns of human subjects research Public Responsibility in Medicine and Research (PRIM&R) - A national organization dedicated to providing a multidisciplinary forum for addressing biomedical and bioethical issues. Conducts training courses for IRB administrators, members and for for investigators and disseminates materials. Institutional Review Board (IRB) Guidebook Online – Produced by DHHS, provides introductory material, regulatory and compliance requirements and information on IRB review of types of research. T he NIH Office of Human Research - Site has information on training for investigators and IRB members as well as standards for protocol review used by the NIH intramural program and lnks to other resources. Videotape "Protecting Human Subjects" – an OHRP resource covering the history of concern about protecting human research subjects, balancing society’s mandates, and the Belmont principles and their application. Almost all universities have IRB Handbooks or Guidelines online. Although these were developed to guide administrators, faculty, students and staff in their institutions, they are available on-line and are excellent resources. Google IRB Handbook or IRB Guidelines to access them or go to the institution’s homepage and search within it for Protection of Human Subjects or IRB. The IRB Forum links to many IRB Home Pages

Institutional Review Board (IRB) Resources

The IRB Forum - A forum sponsored by the Medical College of Wisconsin that promotes the exchange of ethical, regulatory, and policy concerns of human subjects research

Public Responsibility in Medicine and Research (PRIM&R) - A national organization dedicated to providing a multidisciplinary forum for addressing biomedical and bioethical issues. Conducts training courses for IRB administrators, members and for for investigators and disseminates materials.

Institutional Review Board (IRB) Guidebook Online – Produced by DHHS, provides introductory material, regulatory and compliance requirements and information on IRB review of types of research.

T he NIH Office of Human Research - Site has information on training for investigators and IRB members as well as standards for protocol review used by the NIH intramural program and lnks to other resources.

Videotape "Protecting Human Subjects" – an OHRP resource covering the history of concern about protecting human research subjects, balancing society’s mandates, and the Belmont principles and their application.

Almost all universities have IRB Handbooks or Guidelines online. Although these were developed to guide administrators, faculty, students and staff in their institutions, they are available on-line and are excellent resources. Google IRB Handbook or IRB Guidelines to access them or go to the institution’s homepage and search within it for Protection of Human Subjects or IRB. The IRB Forum links to many IRB Home Pages

Ethics: Human Testing University of California San Francisco (UCSF) Human Research Protection Program - links to information on the consent process, federal regulations, training, outside resources and more. The Medical School IRB of the University of Michigan - this site contains links to human subjects research pages, federal regulatory policies, and key ethics source documents Stanford University Research Policy Handbook - on the use of human subjects. University of California Los Angeles (UCLA) Office for the Protection of Research Subjects - includes their comprehensive Investigator Manual for the Protection of Human Subjects Fred Hutchinson Cancer Research Center Institutional Review Office - site provides extensive information about the purpose and necessity of IRB review. University of Minnesota Research Subjects' Protection Programs -- links to IRB and IACUC websites. University of Miami IRB Home Page - site contains information on the protection of human subjects in research, as well as necessary forms and guidelines for conducting such research. Models of IRB Review - Site has information on non-local IRB review of research. National Conference on Alternative IRB Models: Optimizing Human Subjects Protections (2006). A report summarizing the proceedings of a national conference that was suggested by the Secretary's Advisory Committee on Human Research Protections to explore perceived barriers to use of alternative IRB models and to develop means for addressing them. The conference was sponsored by the NIH, the Office for Human Research Protections, the Veterans Administration, AAMC, and the American Society of Clinical Oncology.

University of California San Francisco (UCSF) Human Research Protection Program - links to information on the consent process, federal regulations, training, outside resources and more.

The Medical School IRB of the University of Michigan - this site contains links to human subjects research pages, federal regulatory policies, and key ethics source documents

Stanford University Research Policy Handbook - on the use of human subjects.

University of California Los Angeles (UCLA) Office for the Protection of Research Subjects - includes their comprehensive Investigator Manual for the Protection of Human Subjects

Fred Hutchinson Cancer Research Center Institutional Review Office - site provides extensive information about the purpose and necessity of IRB review.

University of Minnesota Research Subjects' Protection Programs -- links to IRB and IACUC websites. University of Miami IRB Home Page - site contains information on the protection of human subjects in research, as well as necessary forms and guidelines for conducting such research.

Models of IRB Review - Site has information on non-local IRB review of research.

National Conference on Alternative IRB Models: Optimizing Human Subjects Protections (2006). A report summarizing the proceedings of a national conference that was suggested by the Secretary's Advisory Committee on Human Research Protections to explore perceived barriers to use of alternative IRB models and to develop means for addressing them. The conference was sponsored by the NIH, the Office for Human Research Protections, the Veterans Administration, AAMC, and the American Society of Clinical Oncology.

Ethics: Human Testing Ethics Codes and Standards Declaration of Helsinki Nuremberg Code Belmont Report International Conference on Harmonization – Guideline for Good Clinical Practice CIOMS International Ethical Guidelines Canadian Tri-Council Policy Statement Indian Council of Medical Research [PDF]

Ethics Codes and Standards

Declaration of Helsinki

Nuremberg Code

Belmont Report

International Conference on Harmonization – Guideline for Good Clinical Practice

CIOMS International Ethical Guidelines

Canadian Tri-Council Policy Statement

Indian Council of Medical Research [PDF]

Ethics: Human Testing Ethics in Clinical Research (NIH) Ethics & Clinical Trials (NLM Gateway) PUBMED: Ethics and Clinical Trials NIH Clinical Research Policy Analysis & Coordination: Resources/Tools Public Responsibility in Medicine and Research

Ethics in Clinical Research (NIH)

Ethics & Clinical Trials (NLM Gateway)

PUBMED: Ethics and Clinical Trials

NIH Clinical Research Policy Analysis & Coordination: Resources/Tools

Public Responsibility in Medicine and Research

END Class 1, Part 1: Ethics, Human Testing BIOL503 Biotechnology Law and Regulation CSUCI Spring 2009 K. Pessin