History of Research Protections for Individuals and Communities

History of Research Protections for Individuals and Communities Northern Plains Tribal Epidemiology Center Aberdeen Area Tribal Chairmen’s Health Board May 2, 2004

William L. Freeman, MD, MPH, CIP Director of Tribal Community Health Programs, & Human Protections Administrator Northwest Indian College 360-392-4284 fax 360-647-7084 wfreeman@nwic.edu with material by: • Warren Ashe (Howard University) • Jeffrey Cohen (formerly, Office for Human Research Protection--OHRP) • Dale Hammerschmidt (University of Minnesota)

Hy’shqe siam -Thank you, respected teachers • Community members, & community IRB members • Sam Deloria, Lisa Preston, and others • IRB members • Dr. Francine Romero, and others • IRB staff • Helen McGough, Moira Keane, Susan Kornetsky, and others • Researchers • Participants • Carolyn Robbins - Wife

Objectives • To know the basic chronology of the development of the ethics and regulations of protection for individuals in research • To understand the basic intent, nature, and limitations of those regulations • To discuss 3 controversies concerning the regulations • To understand protection of communities in research, and how it can be accomplished

Early problematic research • Infected prostitutes and children with syphilis to test immunity by serum from syphilitic patients, without consent (Germany, 1892) • BCG (TB vaccine) disaster--77 of 256 children died (Germany, late 1920s) • Poor children, especially orphans (1800s-early 1900s, USA & others) • Hebrew Infant Asylum, no orange juice to orphans to study development of scurvy (NYC) • Medical profession changed, to prevent anti-research groundswell • Susan Lederer Subjected to Science: Human Experimentation in America Before the Second World War 1997.

Research atrocities by Nazis, WWII • In concentration camps (Dachau) and killing camps (Auschwitz) • Immerse prisoners in cold water • until they died – the intent of the research • Decompress prisoners in high-altitude chambers • until they died – the intent of the research • Inject many prisoners with typhus • many died • Nuremberg Medical Trial, 1946-47 • tried 23 defendants (20 physicians) • convicted 15

The Nuremberg Code, Aug. 19, 1947 • 10 rules for “Permissible Medical Experiments”: • voluntary consent, without coercion, • good science, done by good scientists, • potential benefits justify experiment, • harms minimized, • degree of risk less than potential benefit, • subjects can end their participation, … [and 4 more] • A start, but with limited applicability: • medical research only, & only on normal subjects • asked "When is research criminal?" • http://www.hhs.gov/ohrp/references/nurcode.htm

After WWII • Radiation experiments (1950s+) • consent absent, or inadequate & deceptive • Willowbrook (1950s) • deliberately infected mentally retarded children with hepatitis virus • coercion of parents • Jewish Chronic Disease Hospital (1960s) • injected live cancer cells into 22 elderly patients, some with dementia, some spoke only Yiddish • consent deceptive, inadequate, & not translated • guardians not asked for permission • Lerner BH. Sins of omission – cancer research without informed consent. NEJM 2004; 351(7):628-630.

Henry Beecher • 1966 article summarized 22 recent unethical medical experiments (out of 50 examples accumulated) • in major medical centers, by prominent researchers, funded by respected sources, published in prestigious journals (including NEJM): • perform heart catheterizations on patients getting a bronchoscopy [look at breathing passages through a tube] • placebo control groups in life-threatening diseases with known effective treatments -- several • randomize soldiers with strep throat to penicillin vs. treatments known-to-be-ineffective [ineffective treatment may lead to rheumatic heart disease] • I.E., ethical problems were mainstream, not fringe • "Ethics and clinical research" NEJM 1966 vol 274, p. 1354-60

US Public Health Service Syphilis Study • Natural history of untreated syphilis in 405 African American men impoverished sharecroppers around Tuskegee, AL 1932-72 • Researchers lied to the men • said they treated them for "bad blood" • Highly "successful" • dropout rate only 1% over 40 years • Why was it so “successful”? • The reason: it was "culturally sensitive" • paid for funeral, African American nurse & some doctors • Not secret! • Updated results published about every 5 years

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research • By the 1974 National Research Act • First, it proposed regulations: • required Institutional Review Boards (IRBs) • for research done or conducted by HEW (now DHHS) • 45 CFR 46 (Title 45 Code of Federal Regulations Chapter 46) http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm

Then issued The Belmont Report • Basic ethical principles underlying its proposed regulations ( - and their application): • Respect for persons • Informed Consent • Beneficence • Assessment of potential risks [harms] and benefits • Justice • Selection of people to be in the research http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.htm

Principle: Beneficence • "Do no harm" - "Do benefit" • Assessment of risks [harms] and benefits • Minimize harms to participants • Use least harmful methods to achieve the scientific end • Favorable Benefit-to-Risk comparison • maximize Benefit:-to-Risk ratio • maximize benefits to participants and society

Principle: Justice • "Treat individuals fairly" • Selection of subjects / participants • Equitable distribution of research harms and benefits • Equitable selection of subjects / participants within a population • Equitable selection of population

Principle: Respect for Persons • "Individual autonomy" • Informed consent • full information • full comprehension • voluntary • without coercion • Protect individuals with reduced capacity to exercise autonomy

CONTROVERSY #1: "The regulations are designed only forexperimental medical research." • A common complaint of some behavioral or non-experimental researchers. • Many ethically problematic studies were medical research. • Let’s examine the sentence: • experimental research; • medical research.

"The regulations are for 'experimental research' only." • Tuskegee was not an experiment. • It was observational research.

Definition of research • "a systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge.... (S)ome demonstration and service programs may include research activities." • 45 CFR 46.102 (d) • The definition is not limited to "experimental." • Nevertheless, were the ethically problematic studies primarily medical research?

Behavioral research with problematic ethics - 1 • Milgram (1963) • Behavioral study of obedience • a few participants still quite distressed when queried well after the experiment • not medical • Humphries (1970) • Tearoom Trade: Impersonal Sex in Public Places • concerns of confidentiality and privacy • neither medical nor experimental

Behavioral research with problematic ethics - 2 • The “Monster Study” so named by people who stutter & researchers of stuttering • by Mary Tudor & Wendell Johnson (1939, unpublished) Randomized trial: 12 normal-speaking orphans in IA orphanage • Researcher purposefully criticized the speech of 6 orphans--to induce stuttering • Some may have developed stuttering, a few for life. • Another example of orphan kids used in research • Franklin Silverman "The monster study" Journal of Fluency Disorders 1988 vol. 13, p. 225-231

Behavioral research with problematic ethics - 3 Social science in the service of eugenics In the state of Vermont [VT], the first third of 20th century Surveys of "dumb" or "delinquent" children and their families “Dumb” or “delinquent” families were usually poor Catholic French Canadians, Abenaki Indians, or migrants Led to VT sterilizing some of the identified “dumb” or “delinquent” children -- "to protect the gene pool" Poor science: did not measure "dumbness" or "delinquency" Nancy L. Gallagher Breeding Better Vermonters: The Eugenics Project in the Green Mountain State 1999. [Please do not turn the page of the handout until asked to do so]

Non-experimental behavioral research - 4 • What do you think has been the general kind of research that has caused the most harm to the most people in 20th century America? • USPHS syphilis study in Tuskegee? • radiation experiments? • eugenics? • other?

My vote • IQ research comparing blacks and others • observational behavioral research (not medical) • contributed to and reinforced racial stigmatization of African Americans and others, including American Indian, Alaska Native, Canadian First Nation, and Inuit students and people • harmed primarily those communities, and all people in those communities • What will historians 40 years from now say about our research today? [Please turn page of handout]

CONCLUSION #1 • All types of research, both experimental and non-experimental, both medical and behavioral, has caused (and can cause) major harms • “Harms to communities”: when community members not in the original research are directly harmed by the results of the research • The IRB should have the expertise to assess all potential harms, including harms to communities, in the research it reviews • behavioral research may require special expertise • e.g., qualitative, ethnographic

CONTROVERSY #2: The place of regulations in human research protection • 1900 - Germany, Prussian Minister of Religious, Educational, and Medical Affairs Directive - included consent "unequivocally" • 1930 - Germany, Reich Minister of the Interior "Regulations on New Therapy and Human Experimentation" • had almost all points in Nuremberg Code Nazis did ethically atrocious research despite regulations Michael Grodin "Historical origins of the Nuremberg Code," in George Annas & Michael Grodin (eds) The Nazi Doctors and the Nuremberg Code 1992 p. 121-144; Paul Weindling "The origins of informed consent: the International Scientific Commission on Medical War Crimes, and the Nuremberg Code" Bulletin of the History of Medicine 2001 vol. 75, p. 37-71.

USA: Medical University IRB - 1 • 1994 - MU IRB reviewed the Prenatal Clinic policy • to test pregnant women with a urine drug screen • without fully informing the women that a positive test would be reported to the court, and • that the court likely would jail test-positive women and could take their newborn and other children • Most were poor black women. • Preliminary outcome results were reported in state medical journal; final results were promised soon • planned to send final results to a major obstetrical journal • "Was this research?"

Medical University IRB - 2 • A few members voted that, by 1994, it had become prospective research, and would have disapproved the protocol, because • the consent process was incomplete and deceptive, and • the potential harm to the women by the procedures outweighed the potential benefit of the research to each woman and society. • The majority voted that it was not research.

Medical University IRB - 3 • Many IRB members felt that, even if it was research, and for all other research on those subjects: • Drug-abusing pregnant women were harming their fetus, • And the women were doing illegal behavior ... • thus “the women did not deserve to be protected” • What is “wrong with this picture”? From the investigation by OPRR in 1994, and discussion with an IRB member, and Edgar O Horger et al "Cocaine in pregnancy: confronting the problem" Journal of the South Carolina Medical Association Oct 1990 vol. 86, p. 527-531. Also the US Supreme Court, March 22, 2001, reviewed a legal case from this project (not about the research), and ruled against the city and MU (Ferguson v. City of Charleston et al).

CONCLUSION #2 • Good regulations are necessary, but are not sufficient, for human research protection. • Also necessary are that researchers and IRB members • understand and agree with the purpose of the regulations, • andapply the regulations to everyone, • especially to people whom society or the IRB members consider to be morally or socially "inferior" • or even despise.

CONTROVERSY #3: What were the good, the bad, & the ugly in AI/AN research – and how to avoid the bad & ugly? • Research with AI/AN people/communities/tribes is not listed in the catalog of problematic research • A common feeling among many tribal people: research has harmed AI/AN people • What is behind that feeling?

Older & current good history / research Tuberculosis was a killer, major cause of AI/AN death • last half 19th, & first half of 20th, centuries • Clinical trial of INH [isoniazid] in the Navajo Rez in early 1950s proved INH was an effective treatment, saved many AI/AN lives Diabetes is a killer - Diabetes Prevention Program [“DPP”] proved that intense counseling for lifestyle change could prevent type 2 diabetes [reduce calories, especially fats; moderate exercise 30 minutes a day 5 times a week; reduce weight by 7%] Community-Based Participatory Research - Kahnawa:ke Schools Diabetes Prevention Project - People Awakening Project with Alaska Native groups, about resiliency and strengths in dealing with alcoholism

Older bad history - 1 • Research with radioactive iodine (I131) early 1950s, USAF "Do ANs survive the cold by having higher metabolism?" • Gave I131 to Alaska Native people • same amount as then used for thyroid scan • almost all ANs did not speak English • 3 AN women in research were breast feeding children! • Long term effects of thyroid scan not then known • (ANs: not higher metabolism; know how to dress and eat) • Involved radiation – a feared modern hazard

Older bad history - 2 • Navajo uranium miners, 1950s • Dust in U mines known to cause lung cancer • AEC refused to regulate mining • PHS study, “natural history” • health exam Q2Yrs, tracked deaths • "pile up bodies at the door" • did not inform participants of known health effects or reason for study • Bodies piled up by 1960s -> regulation started

Implications of older bad history • I131 and uranium studies have complex issues • children who were breast feeding may not have been followed up • so what would you do to get the US to establish health regulations for mining, against the power of the AEC? • The problem was basic protocol design

Recent bad history - 1 • Barrow, Alaska study on alcoholism • 1970s, researchers from northeastern US • announced findings in press conference • held at their northeastern university • Internal stigmatization by people from Barrow & nearby communities • Bonds on Wall Street adversely affected • Impact of research results? • no positive change in/by Barrow

Recent bad history - 2 • Haida Gwai anthropologic research, 1970s? • PhD student -> worked as a schoolteacher • Documented effects of alcohol • incest, murder, etc. • instances not widely or legally known in the community • Book published 1990s, names “hidden” • to outsiders -- but not to community members! • Author almost physically assaulted in next visit

Recent bad history - 3 • Congenital syphilis epidemic, 1980s • Rez not named in publication • gave precise 1980 US Census pop. • Rez children taunted ["Your mama's ..."] • Gas stations refused to let Rez people use restrooms

Recent good & bad history - 4 • Hantavirus, summer 1993 • 50% of infected people died • first recognized on the Navajo Rez • CDC found cause <10 days--a virus from deer mice Good: helped NNDOH develop prevention programs • NNDOH asked CDC not to give Navajo place names in scientific articles Bad: 1st 2 articles, CDC named the Navajo Chapters • where the people lived who were infected first • where the deer mice and other animals were trapped • Navajo approved no research for >13 months

Implications of recent bad history • Major community harm was disruption • Major individual harm was “internal” self-stigmatization • All subsequent research in many of those communities was adversely affected • The problem was publication-dissemination

Current bad research – 1 • Nuu-chah-nulth First Nations [western Vancouver Island, BC, Canada], severe unusual arthritis • early 1980’s, UBC rheumatology & genetic researchers studied their problem, took blood specimens • geneticist kept specimens with him [UBC -> U Utah -> Oxford U], report migration genetic research results • Community found out 3 years ago • major adverse publicity across Canada • Community wanted the specimens back to finish the arthritis research • geneticist died early 2004, had stated to return specimens

Current bad research – 2 • Havasupai • early 1990, tribe approved a diabetes study including genetic analysis, by ASU researchers • no NLM-listed journal articles on genetic analysis of T2DM among Havasupai, one article on nutrition • HLA, inbreeding, & migration genetic research also done using the specimens • sources: • Rubin P. Indian givers. Phoenix New Times 2004; May 27 • Dalton R. When two tribes go to war. Nature 2004; 430:500-2 • Editorial. Tribal culture versus genetics. Nature 2004; 430:489 • Pubmed: Havasupai OR Markow T[Author] OR Martin JF[Author] OR Benyshek D[Author] OR Zuerlein K[Author] • Paul Rubin [personal communication]

Implications of current bad history • The old NIH policy and researcher practice, of sharing genetic specimens [usually anonymized for identity of the individual] is no longer appropriate • “Tribal approval of research” extends to future uses • of genetic & biological specimens • of data • Tribes vary about their degree of favorable or unfavorable attitude toward research in general • extent to which they see research as an enemy of, or a friend of, the tribe’s future physical and cultural survival • The values and relationships of the tribes and researchers are changing

Current ugly research • Havasupai [there is more] • concurrently with T2DM study was schizophrenia study • apparently researchers told neither tribe nor individuals • apparently research team obtained information from clinic charts surreptitiously, after hours, with no approval • apparently the ASU IRB did not comply with own procedures & requirements • Was this “amateur night”? • Now prime example of ugly research in Indian Country • major adverse publicity in Arizona, major law suit by Havasupai Better tribal or IRB review could have prevented this!

Current good research and practices • “Kennewick Man” is an example of bad practice • skeleton found 08/96, 1st scientist said was “caucasoid” • Kwaday Dan Ts’inchi - “Long Ago Man Found” • Champagne-Aishihik First Nations [FN], d. 1415-1445 • glacier in Tatshenshini-Alsek Park, British Columbia [BC] • body found 08/99, plan developed, studied to 12/2000 • returned to the Champagne-Aishihik • cremated, potlatch, ashes scattered where found 07/2001 • head found 08/2003, studied, laid to rest 10/2004 • final ceremonies being planned • FN community + BC government set up a joint group to oversee the research within cultural limits • “People Awakening” Project

Values present in the regulations • Respect for persons • Minimize harms to persons • Maximize benefits to persons • Justice for persons But the regulations [= 45 CFR 46] do not cover: • Publication of private communal knowledge • CDC's Hantavirus articles • Desecration of bones in archaeologic remains • because archaeology is not “human research” – of identifiable living human beings

Native values not explicit in the regulations • Protection of communities except obliquely • Respect for elders & knowledge of community ethnographic interviews published or archived by outsiders • Respect Native communities, strengths, and survival much research focuses on how bad things are not on how/why people survived and do well • Promote resiliency, help activate the community • Respect and promote tribal sovereignty

‘Protect communities,’ ‘respect elders,’ and ‘respect communities’ • Typical research on alcoholism or domestic violence: document how bad things are • attacks the value of community • Rather, research how/why people stopped domestic violence, or became and stayed sober – and thus promote resiliency, help activate the community • People Awakening Project

Rely on others to protect communities? • Yes: • 1967 - Indian Health Service policy required approval by the tribal government of all research • 1976 - "Permission to conduct this investigation was granted by the Indian Health Service, the Bureau of Indian Affairs and appropriate Navajo tribal authorities, including local school boards." • New England Journal of Medicine “Vitamin C and acute illness in Navajo school children” 1976, vol 295, p. 973-977. • No: • Before the publication, the Navajo Area IHS IRB asked CDC to change the Hantavirus articles -> no change • The IHS Research Program Director & Chair of its IRB demanded deletion of the place names -> no deletion

My summary of the evidence - 1 • Some research has been good for AI/AN individuals and tribes • Some research has been bad for AI/AN individuals and tribes • Some research has been both good and bad • Some research has been ugly • The regulations do not include some important AI/AN concerns • Tribes and TCUs need to protect themselves • in addition to relying on others & the regulations

My summary of the evidence - 2 • Researchers are more ethical • IRBs do protect individuals • The regulations are valuable • and should be understood and used • IRBs & the regulations are a floor, not a ceiling • IRBs are necessary and quite valuable, • but they are not sufficient for tribes, tribal people, and TCUs.

History of Research Protections for Individuals and Communities