Use of Human Subjects and Animals in Research

1. Use of Human Subjects and Animals in Research Brad Sutton, Bioengineering bsutton@illinois.edu Jan 31 2014. BIOE 502 Professionalism

3. Outline • Human subjects research • History of guidelines • What makes a Valid study • Recent violation cases • Animal subject research • History of guidelines • Differences with human research • Valid study • Case Studies

4. Human studies research… • New diagnostics/technology • New drugs to treat disease • Determine neural mechanisms of learning • Neural/cognitive effects of aging • Anything that involves a human and/or their identifying information (tissues/cells) and a manipulation of their current state or environment.

5. Human Subject’s research • What considerations should be taken into account when performing experiments on humans?

6. Definition: Human Subject Research • All studies where there is an intervention or interaction with a living person that would not be happening outside the conduct of the experimentation. (Macrina: Scientific Integrity, 2000) • Also includes: • subject-identifiable data • Specimens and samples • Even if not generated directly as part of the study in question

7. History of Regulation of Human Subjects Research International 1947 Nuremberg Code 1964 – 1996 Declaration of Helsinki Federal 1979 Belmont Report 1991 Common Rule

8. History of development of regulation • 1947 Nuremberg Code • Came out of Nuremberg War Criminal Trials • Experimentation without consent • 10 Nuremberg principles • Risk/benefit ratio • Protection of human subjects • Previous animal studies • Investigator qualifications • Subject-initiated withdrawal • Adverse event, termination of study

9. Declaration of Helsinki • Current Declaration of Helsinki • Recognizes that • Medical progress is based on research which ultimately must rest in part on experimentation involving human subjects. • Sets of principles that should guide human subjects research: • In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society. • It is the duty of the physician in medical research to protect the life, health, privacy, and dignity of the human subject. • Medical research is only justified if there is a reasonable likelihood that the populations in which the research is carried out stand to benefit from the results of the research.

10. The Belmont ReportThe National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research s April 18, 1979 Three Basic Ethical Principles: • Respect for Persons the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy. • Beneficence • do not harm • maximize possible benefits and minimize possible harms. • Justice • Fairness of distribution of research benefits and risks

11. Common Rule - 1991 • Health and Human Services, Protection of Human Subjects • Research – a systematic investigation designed to develop or contribute to generalizable knowledge • Human Subject – a living individual about whom an investigator conducting research obtains • data through intervention or interaction with the individual, or • identifiable private information

12. Common Rule - 1991 • Health and Human Services, Protection of Human Subjects • Research – a systematic investigation designed to develop or contribute to generalizable knowledge • Human Subject – a living individual about whom an investigator conducting research obtains • data through intervention or interaction with the individual, or • identifiable private information WHAT ABOUT STUDENTS IN A CLASS???

13. Common Rule • The regulations contain three basic protections for human subjects: • Institutional Assurances • Institutional Review Board (IRB) Review • Informed Consent

14. Common Rule • What is an Institutional Assurance? • Documentation of institutional commitment to comply with the Common Rule • Required from each institution “engaged” in Federally-funded human subjects research • Voluntary agreement to apply Federal regulations to all research

15. Common Rule Criteria for IRB Approval 45CFR46.111 • Risks to subjects are minimized, research design does not unnecessarily expose subjects to risk • Risks are reasonable in relation to anticipated benefits and the importance of the knowledge • Selection of subjects is equitable • Informed consent is sought from each subject or subject’s legally authorized representative • Informed consent is appropriately documented When appropriate: • data collection is monitored to ensure subject safety • privacy and confidentiality of subjects is protected • additional safeguards are included for vulnerable populations http://www.hhs.gov/ohrp/

16. Common Rule • The Consent Process Informed consent is not just signing a consent form to participate in the research – it is an educational process that takes place between the investigator and the prospective subject and/or their legal guardian. Understandable language with opportunities for questions. http://www.hhs.gov/ohrp/

17. History • 1932 Tuskegee syphilis study • Study untreated syphilis in African Americans • No patient consent • Study disguised as free treatment • 1940’s penicillin found as an effective treatment, but study continued until 1973.

18. Key Principles of a valid study • Informed Consent • Risk/benefit considerations • Safeguard of subject’s integrity • Potential Hazards of Study identified

19. Informed Consent • Each subject must be informed of: • Aims • Methods • Anticipated benefits to subject and society • Potential Hazards • Their ability to withdraw at any time without penalty

20. Informed Consent • Consent must be informed • At the level of understanding of the subject • Thorough enough to convey all known risks • What about getting hit by a car crossing the street to participate? • Risks involved in every day life during the time involved in the study are often not disclosed. • Requires comprehension by the subject • MUST BE DOCUMENTED AND WITNESSED • Checklist at: http://www.hhs.gov/ohrp/policy/consentckls.html

21. Informed consent • Consent Issues: • Competent to consent: understand consequences of participation in the study • MUST BE VOLUNTARY = FREE FROM COERCION • Subtle examples: • Family member of cancer patient • Uninsured seeking treatment • Disease where conventional therapy lacks success (or is non-existent) and promising research is enticing • Physician researcher: dependent relationship with patient

22. Elements of a Consent Form:From Common Rule • Basic elements of informed consent • Statement that the study involves research, disclosure of purposes of the research, duration of subject participation, description of procedures • foreseeable risks or discomforts • Benefits to the subject, if any, or to others which can reasonably be expected from the study • Disclosure of appropriate alternative procedures or treatment that may be beneficial to the subject • Statement about maintaining confidentiality of subject information • For more than minimal risk, statement of compensation and medical treatment for AE • Whom to contact for answers about study or in the case of AE, both investigator and IRB contact information • Statement that participation is voluntary, refusal to participate will not penalize subject or result in loss of benefits to the subject. Subject may withdraw from study at any time without penalty. http://www.hhs.gov/ohrp/

23. Example consent form Biomedical Imaging CenterConsent Functional Imaging Template

24. Jan 28, 2011. BIOE 502 Professionalism

25. Safeguard Subject Integrity • Patient name must be removed from data, ie. assign subject identifier • Key for identifier kept in locked cabinet where only principle investigator has access • Other: • Skull stripping head images? • DNA as identifying information?

26. Example: Subject Identity in Genetic Experiments • http://www.bbc.co.uk/news/health-21056647 • Researchers from the Whitehead Institute for Biomedical Research used this freely available data to create a computer program which could match unique markers to surnames. • This was used to hunt through an academic database - the 1,000 genomes project. • It contains the entire genetic code of volunteers who donated their DNA anonymously. The only record is of the donor's age and their home state. • The computer programme, however, could now work out surnames as well. This was enough, combined with a basic internet search, to work out the identities of around 50 people.

27. Oversight and Approval of Protocols: IRB • Institutional Review Board • Committee requirements: • At least 5 members • Not all same profession • 1 nonscientific (ie. lawyer) • 1 not affiliated with institution (community) • Approval of protocols by majority vote

28. Oversight and Approval of Protocols: IRB • Yearly reviews of approved protocols • Makes judgements about: • risk/benefit ratio at least as good as other options. • Adequate informed consent • Adequate involvement of women and minorities • Adequate statistics from the experiment to yield meaningful result

29. Exempt studies • Some studies are exempt from IRB review • Educational settings involving normal educational practices, • Surveys and interviews if the information is recorded anonymously, non-incriminating

30. Special populations • Research involving special populations may have special requirements • Mental illness • Prisoners • Children

31. ENFORCEMENT:(From Investigational Drug Site, but similar mechanisms in non-drug studies) • FDA has used several types of actions to enforce its regulations: (1) obtaining a promise from a researcher to abide by FDA requirements for conducting drug research, (2) invoking a range of restrictions on a researcher’s use of investigational drugs, (3) disqualifying a researcher from the use of investigational drugs, (4) Restricting funding for the research or whole institution (5) criminally prosecuting a researcher

32. Example: Johns Hopkins 2001 • On July 19, 2001 Hopkins received notice that the Office of Human Research Protection was suspending all federally supported medical research projects involving human research at almost all Hopkins institutions. The action was taken three days after the School of Medicine issued a report in which it took full responsibility for the death of a research volunteer. • Healthy volunteer in asthma study died within a month of taking a potential medication, one that had been listed as toxic in books from the 1950’s but not in more recent texts • the principal investigator "made a good faith effort to discover potential toxicities through current standard medical literature searches and textbook reviews." • Conclusion: PI did not perform thorough search on drugs toxicity • Overtaxed IRB was also blamed, did not confirm drug’s lack of toxicity. http://www.jhu.edu/~gazette/2001/jul2301/23human.html

33. Adverse Event: Extreme Example • London, England: March 2006 • Intravenous injections of TGN1412: fight autoimmune diseases and Leukemia • Within 2 hours of being injected 6 subjects had violent reactions, 2 critical, multiple organ failure. • No adverse effects had been found in rabbit and monkey studies • Participants were paid $3500 to participate

34. Bird Flu Vaccine in Poland • http://www.telegraph.co.uk/news/worldnews/europe/poland/2235676/Homeless-people-die-after-bid-flu-va • Medical trial of bird flu vaccine on 350 homeless and poor • Participants received <$5 to be tested with what they thought was a conventional flu vaccine. • Clinic in the area reported 21 deaths in contrast to their normal rate of 8. • News story in July 2008 • Under investigation • Three doctors and 6 nurses facing criminal prosecution.

35. Recent Issues: Close to home • Oxygen-carrying blood substitute, called PolyHeme, is made by Northfield Laboratories in Evanston, Illinois • Experimental blood substitute given to trauma patients • No consent possible • Community education instead of individual consent. • Opt out by wearing blue wristband • Results of study published 3-4 years later, protect IP of Northfield – no significant difference in outcome, three times higher incidence of myocardial infarction. • Wall Street Journal reported that in a previous study 10 of 81 patients suffered heart attack when administered PolyHeme with 2 deaths. • Source: http://www.nature.com/nature/journal/v440/n7083/full/440390b.html

36. Pitt and Seoul National University • Customized embryonic stem cell project • Pitt PI said that no identifiable information was collected and no IRB approval needed. -- Pitt IRB allowed researcher to make determination. • Project involved egg donation, under Korean law beneficial treatments resulting from research have priority to participants in the research-- hence name recorded as a code by Korean researchers. • Paper published in Science in 2005. • Sidenote: Data was fabricated and paper was retracted. • Pitt under scrutiny as no IRB review of project. • “If there is a linking code, there has to be some … affidavit that the researcher will not be given access to the information.” http://pittsburghlive.com/x/tribune-review/s_446555.html

37. Other examples • Financial ties to drug companies, unreported income -- conflict of interest • NEW REPORTING REQUIREMENTS FROM NIH – effective August 2012. • Must have publicly available FCOI information • Drug studies - selective reporting of results • Clinicaltrials.gov – site to register trials before they start. Track results.

38. ANIMAL RESEARCH

39. ANIMAL RESEARCH • Animals as models:

40. ANIMAL RESEARCH • Animals as models: • Similar mechanisms and functions • An example • A copy of system of interest • Controllable environment/history

41. Animals as models • Models could include any or all of: • Simulations based on known physiology • in vitro : cell culture, test tube. • in vivo: • Animal models : model organism • Human volunteers • Patient groups

42. Animal model • Must choose right organism for specific condition • HIV: Cat vs chimpanzee • Chimpanzee closer to human • Chimpanzee does not develop HIV symptoms • Cat does, FIV • Source: http://www.ori.hhs.gov/education/products/Herkert%20(NC%20State)/index.htm

43. Krebs cycle The crucial experiments of Krebs demonstrated the catalytic effect of C4-dicarboxylic and C6-dicarboxylic acids on oxygen uptake by minced pigeon breast muscle. This preparation was chosen after Szent-Gyorgi showed its activity in the metabolism of C4-dicarboxylic acids; moreover, pigeons were plentiful in Sheffield. Kreb’s results and interpretation were questioned by Breusch because he could not find the catalytic effect of citric acid on the oxygen uptake of minced cat muscle. Subsequently, Kreb’s results were verified, and the existence of the cycle was firmly established. In retrospect, the difference between both muscle preparations is based on the fact that pigeon breast muscle is particularly rich in mitochondria, as opposed to the white cat muscle. (Arnost Kleinzeller, “Introduction: The Choice of Non-mammalian Animal Models for Biomedical Research” in Non-mammalian Animal Models for Biomedical Research, Avril D. Woodhead and Katherine Vivirito, Editors, Boca Raton, CRC Press, 1989, p. 3) Source: http://www.ori.hhs.gov/education/products/Herkert%20(NC%20State)/index.htm

44. ANIMAL RESEARCH Test tube vs Mouse - How are they different?

45. ANIMAL RESEARCH • Animals are object’s of moral concern • That concern can span a wide range among individuals • Philosophical arguments rage: • Animals have interests: • Obtain sufficient food • Remain free from pain • Reproducing • Living a normal lifespan • Once again, research is dictated by a risk (cost)/benefit analysis

46. It is common to place an exercise wheel in the cages of rodents—commonly the mouse or rat will “run the treadmill” for hours at a time. How would you assess this, “from the rat’s point of view?” Is the time spent in the wheel an indication of stereotypical behavior due to boredom or psychological stress, a displaced escape mechanism, or a simple enjoyment of activity? Is it possible to know for sure? Does the rodent have an interest in exercise, or a right to it? • Source: http://www.ori.hhs.gov/education/products/Herkert%20(NC%20State)/index.htm

47. APA guidelines • Research With Animals in Psychology "Psychologists undertake research with animals '...with a clear scientific purpose.'    ...There should be a reasonable expectation that the research will a) increase knowledge of the processes underlying the evolution, development, maintenance, alteration, control, or biological significance of behavior, b) increase understanding of the species under study, or c) provide results that benefit the health or welfare of humans or other animals." (APA Guidelines for Ethical Conduct in the Care and Use of Animals, Section VI.A.)

48. History • 1960 Animal Welfare Institute proposes legislation for licensing of animal researchers – not enacted • 1963 NIH publishes voluntary Guide for the Care and Use of Laboratory Animals. • 1966 Animal Welfare Act legislation started • Mandating humane care and treatment for dogs, cats, rabbits, hamsters, guinea pigs, nonhuman primates • 1996 Publication of Guide for the Care and Use of Laboratory Animals by National Academy of Sciences • “The Guide” includes rats and mice.

49. The Guide • Qualifications and training of animal care personnel • Housing requirements • Space recommendations • Social requirements of communal animals • Enriched environments • Temperature, humidity, ventillation, lighting, environmental noise, … • Anesthesia, surgical and post-surgical care • Euthanasia • Establishment of IACUC

50. IACUC • Institutional animal care and use committee • Committee must have at least 3 (or 5) members. Animal welfare act (DHHS policy) • 1 doctor of veterinary medicine • 1 unaffiliated • 1 practicing scientist with animal research experience • 1 nonscientist • Guide requirement • The unaffiliated member must not be a user of laboratory animals