Ethics of Neurodegeneration Research

1. Ethics of Neurodegeneration Research RE|Nous 11/21/13 Greg Lieberman & Jasmine Toor

2. Outline Declaration of Helsinki History, Policies and Laws Types of ethical issues (Researcher’s perspective) Ethics behind interventional studies Conclusion

3. Resources • Declaration of Helsinki: http://www.wma.net/en/30publications/10policies/b3/ • Development and expansion of US clinical trials http://clinicaltrials.gov/ct2/about-site/history • UntappedEthicalResources for NeurodegenerationResearchhttp://www.biomedcentral.com/1472-6939/12/9 • From chemical to drug: neurodegenerationdrug screening and the ethics of clinical trials http://www.nature.com/neuro/journal/v5/n11s/full/nn931.html

4. Declaration of Helsinki Adopted by the 18th World Medical Association in June of 1964 in Helsinki, Finland Last Amendment occurred by the 64th WMA in October of 2013 Purpose was to set aside ethical principles for medical research with human subjects Most recent revisions include increased protection for vulnerable groups and more protection for participants. https://sites.google.com/a/jozifamilymedicine.org.za/woncaafrica1/family-medicine-in-africa/useful-stuff/changesmadetothedeclarationofhelsinki

5. Declaration of Helsinki

6. History, Policies and Laws 1997 FDAMA- The first US federal law to require trial registration Required NIH to create a public information source on trials regulated by FDA 2005- International Committee of Medical Journal Editors requires trial registration as a condition for publication 2006- World Health Organization establishes trial registration policy 2007- Congress passes law (FDAAA). Required more types of trials to be registered, additional trial registration information, and submission of summary results.

7. Helsinki Revisions 2008- WMA amended the Declaration of Helsinki. Added two new principles: making prospective registration and public disclosure of steady results to be ethical obligations 2013- Modified the 2008 amendments. “Every research study involving human subjects must be registered in a publicly accessible database before recruitment of the first subject.” Researchers need to make their results publicly available with accuracy and completeness.

8. Types of Ethical Issues • Traditional Research Ethics • Subject confidentiality, privacy, and obtaining informed consent. • Heads of research groups found these most important compared to researchers in other positions • New and developing field (neuroethics). Goal is to assess the ethical legal and social implications of research • External influences • Government and public research sponsors and the influence of industry sponsorship on direction and topic of research

9. Types of Ethical Issues

10. Ethics Related Motivators • Ensuring public understanding • Person’s right to be informed about neuroscience advances • Mitigating false hopes or expectations by subjects • External forces • Professional advancement • Chance of publication success • Institutional encouragement • Requirements • Obligations to the research institution • Obligations to research sponsors • Values • Personal values • Feeling that being concerned with ethics is “the right thing to do” • Press and Public • Motivators related to coverage in the press • Positive public perception

11. Ethics Related Motivators

12. Ethics Related Barriers • Resources • Lack of resources and expertise • Burden • Lack of time • Increased administrative work • Concern • Ethics are not relevant to the research • Interest • Lack of interest in ethics from researcher and colleagues

13. Ethics Related Barriers

14. Overall Findings From Study Neuroscientists working in the field of neurodegenerative diseases are motivated and willing to consider ethical issues related to their work and are motived in ensuring public understanding of their research However, for researchers specifically in drug discovery, a perceived lack of ethics resources is a significant barrier to pursuing these interests and goals.

15. Ethics Behind Interventional Studies Central Question: How much is needed to know about a drug before proposing a clinical trial? Common assumption is that a drug needs extensive experimentation to remove all doubt before it is tried in patients. All drugs have side effects so if this condition were to be imposed, no drugs would make it into a clinical trial.

16. Promise of FDA- Approved Drugs Drugs must be tested very thoroughly in-vitro and in model systems before human consumption Drugs that are already approved for another human disease can be more easily tested in patients than untried compounds Success in-vitro or model organisms is not sufficient considering the large investment in time, money and patient recruitment necessary for clinical trials

17. Uncertainty in Animal Models No animal models so far have shown that the same drug is effective in both human and animal counterpart (no predictive validity). Possible factors: follow up time, outcome measures, differences between humans and experimental animals in drug dose, metabolism, and route of delivery. “Until a correlation between human disease and the animal model is demonstrated by a successful clinical trial, we cannot properly guess and the meaning of negative results in animals.”

18. Uncertainty and Equipose Equipose- description of the necessary prior uncertainty that surrounds the outcome of a clinical trial To be “in equipose” the researcher must not know if one treatment is better than another and provide the better treatment to one group rather than another. “Clinical trials are not simply a conformation of pre-clinical observations about a drug’s benefit, but a test of the underlying hypothesis and its relevance to human subjects.” Unethical to have an effective drug and unnecessarily delay clinical testing. On the contrary testing of a drug should not be rushed after insufficient verification Uncertainty is what makes clinical trials necessary and also ethical.

19. Balancing Risk and Benefit • Need a drug with promising results in order to move forward with human trials, but also must weigh against the considerations • Severity of disease • Availability of alternative treatments • Opportunity costs • Trials are bound to have many failures but research can have an additive effect with multiple treatments providing small benefits

20. Conclusion The Declaration of Helsinki laid a comprehensive foundation for ethical consideration in clinical trials Ethics related motivators and barriers are major factors in clinical trials Interventional studies require significant testing in model systems in order to remove as much doubt as possible before subjecting humans to such treatments. Negative results are inevitable in trials but should not deter progress Researchers want to be ethical, but it is important that they do not place the success of their study over the rights of their patients.