Monika S. Markowitz, PhD, MA, MSN, RN Director, Office of Research Compliance and Education Office of the Vice President for Research

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1 Monika S. Markowitz, PhD, MA, MSN, RN Director, Office of Research Compliance and Education Office of the Vice President for Research Quincy J. Byrdsong, EdD, CIM, CIP, CCRP Executive Director of Research Administration for the Virginia Commonwealth University Medical Center

2 Recognize ethical considerations in research arising from a checkered history Identify particular areas of research that present ethical issues for investigators and subjects Using case analyses, distinguish ethical considerations from regulatory requirements

3 Studied Nazi medical experiments U.S. was also guilty of violating research participants rights Ethics and Clinical Research (NEJM 1966) Prompted NIH and FDA to revise guidelines

4 Placebo-controlled studies of strep throat Relapse rate of typhoid fever Acne study including mentally-retarded and juvenile delinquent children Cyclopropane anesthesia and cardiac arrhythmias Study of untreated hepatitis

5 Subject assignment/recruitment coercive Withholding information or treatment Exposure of participants to risks unnecessarily Risks to subjects excessive compared to potential benefits Lack of adequate informed consent

6 Respect for persons informed consent privacy & confidentiality Beneficence benefit/risk or burden assessment Justice distribution of risk and benefit inclusion/exclusion

7 Federal Regulations stemming from Belmont Principles 45 CFR 46 DHHS Policy for Protection of Human Research Subjects 21CFR50, 56, etc. drugs, devices, biologics The Common Rule 45CFR46 Subpart A - adopted by 17 federal agencies, including FDA, in 1991

8 BMR examples: Assignment of participants Use of placebos Involving vulnerable populations Informed consent process Research payment Genetic research Registries privacy & confidentiality over time SBER examples: Assignment of participants Involves deception Involving vulnerable populations Informed consent process Research payment Incidental findings Internet privacy & confidentiality

9 Experimental or control Single-blind, double blind, or open label Randomized or non-randomized Healthy volunteers (Phase I); participants with the condition the article is designed to treat (Phase II and III); and participants either prospectively or already receiving FDAapproved drugs and evaluated post-marketing (Phase IV)

10 Superiority of one treatment/intervention over another Comparing two treatments/interventions that are inferior to a third unless third treatment is contraindicated Current or likely dispute; study designed to help resolve the dispute Ethics of double blinding, when to break blind

11 No available therapy No therapies shown to be superior Current treatment and/or standard of care is ineffective placebo washout Placebo contents known/disclosed?

12 Intended for prospect of direct benefit or for benefit of the sub-population; minimal risk. If the research is greater than minimal risk with no intent or prospect of benefit, the study must have an additional level of approval. Do additional regulatory hoops impact considerations of justice?

13 Prisoners, Group Homes, Facilities Issues of informed consent: Even if not decisionally impaired, may not have full autonomy Consider coercion on either side Risks & benefits of study involvement Why should they participate? If LAR required, legal AND ethical? Issues of privacy/confidentiality Very difficult in prisons or among dependent populations Impact if privacy cannot be assured Implications of breached confidentiality

14 Increased chance of coercion or undue influence (e.g. better care in research) Usually more than minimal risk with benefits unlikely or unclear Overprotective, unjustified regulatory oversight? Inadequate informed consent process and exceptions (e.g. comatose patients)

15 Ethical obligations to include if prospect of direct benefit? Is the short form consent adequate? On-going presence of interpreter Is it safe if a high risk study? Ethical obligations to include if nontherapeutic?

16 Honesty, particularly about benefits Encourage inclusion of family members in decision-making Transparency about financial incentives Reasonable monetary compensation or consider alternatives Poverty illiteracy/low intellect

17 Obtaining on-going informed consent Likelihood of receiving experimental treatment after study is completed? Consequences of randomization Relationship to SOC or other therapeutic regimens particularly as it relates to risks and benefits Decisionally-impaired adult Consent for unspecified, future research?

18 Assent how complete should it be? When is assent documentation meaningful? No means no when? Aging up do we think about consent? Parental permission when do parents not need to be informed? Due diligence in finding parents/legal guardians

19 Access to protected health information Limited patients for many studies Contact with potential research subjects Notification of eligibility to subjects by clinicians Delineation between subjects who wish to be contacted and subjects who do not wish to be contacted Balance between confidentiality of subjects participation and patient safety Increased time commitment of explaining risk-benefit situation

20 Electronic privacy concerns Confidentiality of data subject to limited access; built in protections Long term maintenance of registries Research utilizing social networks, virtual worlds HIPAA adding a regulatory layer unanticipated by Common Rule

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22 A study of a drug that prevents breast cancer is proposed for young, healthy volunteers who are at risk for breast cancer. Some side effects of the drug are ovarian cancer and liver disease.

23 An investigator is conducting a randomized placebo controlled study of a investigational treatment for a memory disorder. The study will last 5 years. Part of the screening will be an assessment of the subject s ability to consent for themselves. The informed consent requires signatures for the subject and a legally authorized representative.

24 A PhD investigator was exploring the brain s processing of various neurotransmitters while 5 healthy subjects viewed a series of photographs under different kinds of environmental conditions. The MRI for 1 subject unmistakably revealed a brain tumor. There was no plan to interact again with the subjects after the MRI. How should this incidental finding be dealt with?

25 An investigator is conducting an investigational vaccine study in children between the ages of two and five. The physicians and staff in the clinic are ethnically diverse. Over 85% of the patients seen in the pediatric clinic are Korean and speak very little English. The investigator has translated permission forms to the appropriate language but interpreters are community volunteers, not employed by the facility.

26 22 children in the custody of the state were told they were to receive speech therapy. Instead they were placed in intervention and control groups, to try to induce stuttering in healthy children and to see whether stutterers would improve if told that their speech was fine. Many of the normal speaking orphan children who received negative therapy in the experiment suffered negative psychological effects and some retained speech problems for the rest of their lives. University of Iowa publicly apologized for the Monster Study in 2001.

27 A smoking sub-study is conducted as an extension of a study of abused women. A procedure involves a saliva sample to measure the level of cotinine resulting from nicotine intake. In actuality, the researcher is measuring stress hormone levels.

28 A 64-year-old man presents with advanced lung cancer. He has a long history of depression, resulting in several suicide attempts. There is currently no treatment to statistically prolong life with his cancer, but his oncologist has a protocol for a new therapy. The subject s brother and legal guardian wants him to participate but the subject who is clinically depressed refuses and states he is not interested in therapy. His psychiatrist is concerned that this may be a subtle way of committing suicide. Macrina, Scientific Integrity

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